CNS Agents 101 Overview Recent Developments in Anxiolytics Jens Perregaard*, Connie SBnchez and J@m Amt Research and Development, H Lundbeck NS, Ottiliavej 9, DK-2500 Copenhagen-Valby, Denmark *Author to whom correspondence should be addressed Current Opinion in Therapeutic Patents January 1993 introduction In this review recent developments in the search for new anxiolytic agents, including phar- macological test models, mechanisms of action and chemical classes of compounds are dis- cussed. Patents claiming anxiolytic agents published in the period from August 1991 to Au- gust 1992 are categorized and reviewed within this classification. Since their introduction in the early 1960’s, benzodiazepines have progressively and com- pletely superseded the barbiturates and have become the predominant therapy for the treat- ment of anxiety. However, concerns of the risks of tolerance and physical dependence [ 1,2] associated with this medication have stimulated much effort in the development of new anxi- olytic drugs. Side-effects such as abuse and dependence, sedation, impaired performance, al- cohol interaction and withdrawal symptoms, including rebound anxiety, are hardly acceptable in modem medication. Additionally, anxioselectivity without the sedative, anticonvulsant, and muscle relaxant properties associated with benzodiazepines is desirable for a new anxiolytic drug. Consequently, research activities have intensified; this is reflected in the vast number of patent applications filed during this last year. About 150 applications, most of them includ- ing novel compounds, claim new possibilities for the treatment of anxiety. Many mechanistic aspects are being pursued, but until now only one compound with a different mechanism of action, buspirone, has reached the market. Anxietv Disorders Anxiety is one of the most frequent h u m a emotions. Anxiety may be a normal condition in man, a symptom observed in different physical diseases, or a separate psychopathological condition. The symptoms of anxiety are well known and affect different levels of biological activity, i.e. affective-cognitive, vegetative, endocrine, motor and behavioural levels. Anxiety disorders may be described as long-lasting states of anxiety in the absence of actual danger or stressors, or as an exaggerated emotional response to normal stimuli. A large number of epi- demiological studies of anxiety disorders have been performed. Anxiety disorders frequently begin between the ages of 20-30 and can be triggered by life events. The course is often characterized by a certain chronicity that manifests itself in residual symptoms and mild im- pairment in social roles, and is frequently complicated by depression. The patient population is heterogenous and can be classified into various subtypes of anxiety. A number of diagnos- tic classification systems exists. However, the most generally accepted and frequently used diagnostic system is the one suggested in DSM-III-R [3]. DSM-III-R distinguishes between several types of anxiety disorders, e.g. generalized anxiety disorder (GAD), panic disorder (PD) with or without agoraphobia, obsessive-compulsive disorder (OCD), and other phobias. The following discussion of pharmacotherapy of anxiety will concentrate on these definitions. 0 Current Drugs Ltd ISSN 0962-2594 Expert Opin. Ther. Patents Downloaded from informahealthcare.com by University of Limerick on 04/15/13 For personal use only.
Transcript
CNS Agents 101
Overview
Recent Developments in Anxiolytics Jens Perregaard*, Connie SBnchez and J@m Amt
Research and Development, H Lundbeck N S , Ottiliavej 9, DK-2500 Copenhagen-Valby, Denmark
*Author to whom correspondence should be addressed Current Opinion in Therapeutic Patents January 1993
introduction
In this review recent developments in the search for new anxiolytic agents, including phar- macological test models, mechanisms of action and chemical classes of compounds are dis- cussed. Patents claiming anxiolytic agents published in the period from August 1991 to Au- gust 1992 are categorized and reviewed within this classification.
Since their introduction in the early 1960’s, benzodiazepines have progressively and com- pletely superseded the barbiturates and have become the predominant therapy for the treat- ment of anxiety. However, concerns of the risks of tolerance and physical dependence [ 1,2] associated with this medication have stimulated much effort in the development of new anxi- olytic drugs. Side-effects such as abuse and dependence, sedation, impaired performance, al- cohol interaction and withdrawal symptoms, including rebound anxiety, are hardly acceptable in modem medication. Additionally, anxioselectivity without the sedative, anticonvulsant, and muscle relaxant properties associated with benzodiazepines is desirable for a new anxiolytic drug. Consequently, research activities have intensified; this is reflected in the vast number of patent applications filed during this last year. About 150 applications, most of them includ- ing novel compounds, claim new possibilities for the treatment of anxiety. Many mechanistic aspects are being pursued, but until now only one compound with a different mechanism of action, buspirone, has reached the market.
Anxietv Disorders
Anxiety is one of the most frequent h u m a emotions. Anxiety may be a normal condition in man, a symptom observed in different physical diseases, or a separate psychopathological condition. The symptoms of anxiety are well known and affect different levels of biological activity, i.e. affective-cognitive, vegetative, endocrine, motor and behavioural levels. Anxiety disorders may be described as long-lasting states of anxiety in the absence of actual danger or stressors, or as an exaggerated emotional response to normal stimuli. A large number of epi- demiological studies of anxiety disorders have been performed. Anxiety disorders frequently begin between the ages of 20-30 and can be triggered by life events. The course is often characterized by a certain chronicity that manifests itself in residual symptoms and mild im- pairment in social roles, and is frequently complicated by depression. The patient population is heterogenous and can be classified into various subtypes of anxiety. A number of diagnos- tic classification systems exists. However, the most generally accepted and frequently used diagnostic system is the one suggested in DSM-III-R [3]. DSM-III-R distinguishes between several types of anxiety disorders, e.g. generalized anxiety disorder (GAD), panic disorder (PD) with or without agoraphobia, obsessive-compulsive disorder (OCD), and other phobias. The following discussion of pharmacotherapy of anxiety will concentrate on these definitions.
Anxiolytic test models There are probably more animal models of anxiety disorders than of any other mental dis- order. The models may be classified according to the type of anxiogenic stimulus used (i.e. innate fear stimuli or secondary aversive stimuli), the type of behaviour observed (i.e. primary drives (e.g. thirst, hunger) or exploratory and social behaviour), and the response obtained (i.e. induction or suppression of behaviour). A number of the more frequently used animal models and the effects obtained with various pharmacological classes of substances are listed in Table 1.
Table 1. Test models in animals for anxiolytic activity of different classes of compounds.
~ - H T , A 5-HTZ 5-HT3 BZ CCK, EAA References
INNATE AVERSIVE STIMULI 1. Increased response ultrasonic vocalization raffmouse pups marmoset human threat 2. Suppressed response elevated plus maze
Consistent effects are shown with benzodiazepines, whereas anxiolytic effects with the new generation of non-benzodiazepine anxiolytics are less consistent in the animal models. This, of course, questions the validity of the models. Only a few of the animal models of anxiety have been extensively validated. A study measuring the degree of stressfulness by increases of plasma corticosterone concentration showed that the punished drinking test (Vogel’s conflict test) is much more stressful than the social interaction test and the elevated plus maze test [40]. This may explain at least some of the different effects obtained with various drugs. Furthermore, the relationship between animal models and subtypes of anxiety is generally not understood. However, lactate can induce panic attacks in macaque monkeys, which can be prevented by imipramine [41].
It is important to note that anxiety states in man are the result of cumulative interactions of personality traits with the environment. Most animal models focus on state anxiety (i.e. the anxiety experienced at a particular moment depending on the presence of an anxiogenic stimu- lus), and do not put emphasis on trait anxiety (i.e. an invariable feature of an individual) [24]. There is evidence from animal experiments that long-lasting impairment of the neuronal sys- tems (e.g. protein malnutrition) affects emotional behaviour [42]. Animal models of chronic anxiety and fearlessness based on knowledge of the ontogeny of benzodiazepine receptors have been described [43]. In most animal models anxiety is investigated in an unselected population of animals, whereas clinical efficacy of anxiolytics is shown in a population of
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CNS Agents 103
anxious patients. Genetic selection studies of rats based on open field behaviour were first performed in the fifties resulting in the so-called Maudsley Reactive (anxious) and Nonreac- tive strains [24]. A genetic animal model of anxiety in pointer dogs has also been suggested [44]. Animal models need to be further developed in order to comply with the characteristics of anxiety disorders.
Test models for side-effects A major breakthrough in the treatment of anxiety would be to reduce side-effect liability for a new anxiolytic agent compared to benzodiazepines. Thus, animal models detecting such side-effects are crucial. Withdrawal responses can be detected in a variety of animal species on termination of drug treatment. Characteristic symptoms in rats upon withdrawal of ben- zodiazepines are twitches, tremor, piloerection, vocalization, startle, weight loss, myoclonic jerks, hyperactivity and hostility. Most of the symptoms are observed in animals after very large doses of benzodiazepines. However, increased anxiety and changes in seizure threshold can be detected after treatment with low doses, which are more relevant to clinical treat- ment [45]. Increased anxiety levels upon withdrawal have been demonstrated in a number of different animal models (e.g. elevated plus maze, explorative behaviour in blacWwhite box, different conflict tests, social interaction test, ultrasonic vocalization test) [45,46]. Self- administration studies in rats or primates may be used to demonstrate dependence-inducing potential of a drug [47]. However, the drug-conditioned place-preference test has become the test of first choice in many laboratories. Place-preference can be induced by a large number of drugs subject to abuse, e.g. diazepam, ethanol, amphetamine, cocaine, morphine, nicotine and phencyclidine [48].
Sedation is one of the most common side-effects of benzodiazepines. Alcohol interaction is also a well known side-effect. A number of simple test models are available to detect motor impairment, e.g. rotarod and traction (horizontal wire).
Benzodiazepine-induced amnesia may be detected in different animal models of cognitive impairment, e.g. passive avoidance, spatial learning tasks such as Morris’ water maze. De- velopment of tolerance to sedative, anticonvulsant and anxiolytic effects of benzodiazepines is known from animal experiments and clinical experience [45]. The time periods for devel- opment of tolerance probably depend on the effect studied, i.e. tolerance to sedative effects develops very rapidly while tolerance to the other effects seems to develop more slowly.
Mechanisms of Anxiolvtic Action
Like other mental disorders, human anxiety probably represents a set of phenomena that are not related to a single biological substrate. Studies of the mechanism of action of benzodi- azepines have indicated various methods by which the therapeutic profile of anxiolytic drugs may be improved; the main target is to reduce some of the undesired effects. Nonbenzodi- azepine drugs, e.g. antidepressants for treatment of certain forms of anxiety (PD, OCD) have also been used with some success [49,50].
The ascending serotonergic raphe system and noradrenergic locus coeruleus pathways are suggested to play important roles in states of anxiety [51]. Close interactions between the brainstem areas containing medullary chemoreceptors, the noradrenergic locus coeruleus and the serotonergic dorsal raphe nuclei are believed to be involved in the pathogenesis of panic attacks [41].
Serotonin (5-HT) According to the classical hypothesis, serotonin function is increased during anxiety states [52]. There is increasing clinical evidence for serotonergic involvement in GAD, PD, and OCD [49,50,52]. Benzodiazepines reduce 5-HT function in man. Challenge studies with the 5-HT1 agonist m-chlorophenyl- 1 -piperazine (m-CPP) have demonstrated exaggerated psy- chological and endocrine responses in panic disorder patients, and increased anxiety in nor- mal volunteers and patients with OCD [53]. Anxiety research mainly focuses on ~ - H T ~ A , 5-HT2/1~, and 5-HT3 subtypes of serotonin receptors and 5-HT-uptake inhibition. ~ - H T ~ A receptor agonists are clinically effective in the treatment of GAD [54], 5-HT-uptake inhibitors have therapeutic efficacy in PD, and effects of chlorimipramine and more selective 5-HT-up- take inhibitors in OCD have been consistently observed [53]. Treatment with drugs facilitating the serotonergic function may initially induce an exacerbation of anxiety; subsequently there is a latency of several weeks for the onset of anxiolytic effects [49]. Serotonergic ligands and their in vitro specificities for subtypes of serotonin receptors have recently been reviewed by Wijngaarden et al. [55].
5-HT1* agonistslantagonists
The anxiolytic action of 5 - H T 1 ~ agonists may be mediated by different mechanisms of ac- tion. A reduction of 5-HT release by stimulation of somatodendritic ~ - H T ~ A autoreceptors in the dorsal raphe has been proposed as a possible mechanism [49]. However, development of subsensitivity of 5-HT receptors after chronic treatment leading to increased serotonergic activity has also been suggested [49]. The latter mechanism is consistent with the slow on- set of action. The ~ - H T ~ A agonists in clinical development also appear to possess the 5-HT enhancing ability characteristic of antidepressant agents, i.e. desensitization of somatoden- dritic 5-HT autoreceptors [50,56]. These different properties may be explained by the partial agonism observed with these drugs. PD patients exhibit significantly attenuated thermoregu- latory and neuroendocrine responses to ipsapirone, suggesting decreased function of both the pre- and postsynaptic 5-HT1* receptor-effector system [57].
Serotonin ~ - H T ~ A ligands are the most extensively studied class of anxiolytic compounds. These research efforts are reflected in more than forty patent applications appearing during the last year. Bristol-Myers’ buspirone (la) [58,59], a partial ~ - H T ~ A agonist, has been available for some years on several markets. Its therapeutic efficacy in the treatment of GAD is compa- rable with that of the benzodiazepines [60-631. None of the side-effects of benzodiazepines mentioned in the introduction have been found with buspirone. However, buspirone is not the ultimate anxiolytic drug. The onset of action (1 -3 weeks) is considerably slower than that of the benzodiazepines [63,64]. Patients treated with benzodiazepines for longer periods do not respond to subsequent buspirone treatment [65]. Buspirone was originally invented as a potential antipsychotic [59] and the anxiolytic effect was found by serendipity. After its anxiolytic effects had been clinically proven [62], the interaction with ~ - H T ~ A receptors was demonstrated [66].
In recent years, the mechanism of anxiolytic action of buspirone has been questioned due to the fact that it is subject to substantial first pass metabolism [61]. An oral bioavailability of only 4% has been estimated. The primary metabolite, 1 -(2-pyrimidyl)piperazine (1 -PP), is an a2-antagonist [61,67,68]. Combinations of ~ - H T ~ A agonists and a2-antagonists (e.g. 1 -PP or idazoxan) have recently been claimed by Pfizer to have a synergistic anxiolytic effect [201]. It is unlikely that the major drawbacks of buspirone will be resolved by the next generation of
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CNS Agents 105
partial 5-HT1 A agonists which are in late clinical development. These compounds have very similar pharmacological profiles and all share the 1 -(2-pyrimidyl)-4-butylpiperazine structure. Such compounds include Bristol-Myers’ gepirone (lb) [69], Bayers’ ipsapirone (lc) [56], SumitomoPfizer’s tandospirone (Id) [70,71], all reported to be in Phase I11 clinical trials, and Wyeth’s zalospirone (le) [72] and Esteve’s lesopitron (If) [8] which are probably in Phase MI clinical trials. Esteve has recently disclosed very close analogues of lesopitron which differ in replacement of the 4-chloropyrazole ring with, for example, a benzimidazole [202].
la buspirone 1 b gepirone lc ipsapirone
- N O D -No- - N P c ’
0 0
cpu R =
1
I Id tandospirone le zalospirone I f lesopitron
Many 1-arylpiperazines with potent affinity for ~ - H T ~ A receptors have been reported. Wyeth has introduced aryl substituents at positions 2 or 3 in the side chain of structures 3- 6 [203-2051. These compounds are related to the nonselective putative ~ - H T ~ A antago- nist NAN- 190 (2) “731. Interestingly, antagonistic properties have also been demonstrated for the Wyeth compounds. Inhibition of 8-OH-DPAT-induced 5-HT syndrome was indi- cated for compounds represented by 3 [203]. Anxiolytic effects were shown in the mouse blacWwhite box with the butyryl derivative (n=2) being the most potent. A related com- pound (7, WAY-100,135) was reported to be an antagonist at ~-HT~,L, autoreceptors in the dorsal raphe nucleus. Pretreatment with 7 attenuated 8-OH-DPAT-induced reduction in 5- HT neuronal firing [74]. In contrast to the Wyeth compound, NAN-190 reduced neuro- nal activity in this area indicating agonistic properties. In a homologous series (4) con- traction of guinea pig ileum induced by 5-carboxamidotryptamine was blocked at nanomo- lar concentrations [204]. 1 -(2-Methoxyphenyl)piperazines have also been disclosed by Faes [206]; however, anxiolytic data were not given. Methoxynaphthylpiperazines (8) claimed by Novo Nordisk are potent ~ - H T ~ A ligands [207], without being selective (high D2 and 5- HT2 receptor affinities). Within this series of compounds, 5-HT2 antagonists with no affinity for ~ - H T ~ A receptors were also found (e.g. 4-(2-chlorophenyl)-l-[3-(3,4,5-trimethoxyphenyl- carbamoyloxy)propyl]piperazine). No anxiolytic data were provided. Selective ~-HT~,L, lig- ands similarly derived from 1 -(7-methoxynaphth- 1 -yl)piperazine were previously reported by Servier: S 14671 [75] and S 14506 [76]. Actually, the piperidyl analogue (9) of S 14506 was recently disclosed by Adir [208], mainly focusing on antihypertensive effects. Very simi- lar analogues of buspirone have been claimed: thienoazapinones (10) [209], 1,4-benzodiaza- pinones (lla)/l,4-benzothiazepinones (llb) [210], and the azabicyclooctanone 12 [211]. As would be expected, low nanomolar ~ - H T ~ A receptor affinity [209,210] and activity in conflict models [209,211] and in the blacwwhite box [211] were reported for these compounds. SUN 8389, which is the 1,4-benzoxazepine-3,5-dione analogue of 11, was previously claimed as
a ~ - H T ~ A receptor selective compound with anxiolytic (social interaction and anticonflict) activity [77]. Affinity for 0-receptors (see later) was claimed for compounds l l a and l l b by Suntory in a subsequent application [212]. In compound 13 [213], ~ - H T ~ A affinity is retained by combining the azaspirodecane moiety of buspirone with the mixed ~ - H T ~ A , B , c agonist 1 - (3-trifluoromethylphenyl)-piperazine (TFMPP) [78].
Benzodioxanes and related structures derived from Duphar’s flesinoxan (14) [79] or Merrell Dow’s binospirone (15) [80] have been claimed [214-2231. Flesinoxan is a full ~ - H T ~ A ag- onist with anxiolytic activity in some animal models (Geller-Seifert conflict test in pigeon, anticipatory anxiety in mice, ultrasonic vocalizations in rat pups) [79]. Compared with %OH- DPAT and other full ~ - H T ~ A agonists, flesinoxan induces only insignificant 5-HT syndrome [81]. It will be interesting to learn if the higher oral bioavailability and higher receptor ef- ficacy of flesinoxan in rodents compared to the pyrimidylpiperazines will result in better anxiolytic efficacy in man. AdidServier [82,214] has reported 5-HT1* antagonists in a series of 5-( 1 -piperazinyl)benzodioxanes (16) which block 8-OH-DPAT-induced behaviours. These compounds resemble low efficacy 5 - H T l ~ agonists (17) previously disclosed by Lundbeck [83,215]. 2-Substituted benzodioxanes include follow-up compounds 18 [216] to Mitsubishi’s BP-554 [ 841. Anticonflict activity in Vogel’s conflict test was shown. Upjohn’s indolodiox- anes (19) are combinations with spiperone fragments and thus exhibit nanomolar affinity for both 5-HT1* and dopamine D2 receptors [85,217]. Anxiolytic potential was claimed but no data are provided. Further benzodioxan-2-ylmethylamine derivatives were claimed by Amer- ican Home Products [218], Adir [219], and Merrell Dow [220]. The benzodioxane part of binospirone can be successfully replaced by 5-hydroxy- or 5-methoxy-tryptamine, as shown by Novo Nordisk [221], Adir [219], and Merrell Dow [220], and exemplified in structure 20, or as shown by American Home Products [222], in benzofurans 21. Such compounds are high-affinity ~ - H T ~ A ligands, but no documentation for anxiolytic activity in animals was provided. Adir has prepared a large number of benzoxazines and related derivatives 22 [223]. Subnanomolar ~ - H T ~ A receptor affinity and marked anticonflict activity in pigeons were claimed in general, but no specific test results were shown.
8-OH-DPAT (23), the prototype of a 5 - H T l ~ agonist, has also been mimicked in recently disclosed structures. The oral bioavailability in rats of 8-OH-DPAT is negligible due to fast and extensive first pass metabolism by conjugation (P-glucoronidation) and N-depropylation [86]. Many companies have attempted to overcome these unfavourable properties. Upjohn and Lilly have replaced the phenolic 8-OH substituent in structures 24-26 [224-2261. For the formylindole derivative (24) an oral bioavailability of 48% was achieved. However, this compound was later reported to have mutagenic effect in Ames test [87]. Many of the Lilly compounds (25) were shown to have nanomolar affinity for ~ - H T ~ D , as well as for 5-HT1*, receptors. An exception is the clinical development candidate LY 178210, which has 500-fold less affinity for ~ - H T ~ D receptors than for ~ - H T ~ A receptors [88]. The anxiolytic significance of the ~ - H T ~ D component is unknown since only receptor binding data were provided. Close azetidine analogues (27) of 8-OH-DPAT have been claimed by Wyeth [227], while Abbott has incorporated the amine nitrogen atom in a further condensed ring [228]. Only receptor affinities and antihypertensive effects were demonstrated.
P-Adrenoceptor antagonists, such as (-)-pindolo1 (28), (-)-propranolol, and (-)- penbutulol were among the first compounds to show antagonistic effects at ~ - H T ~ A receptors. How- ever, these compounds, except (-)-penbutulol, also possess partial agonist properties in some test models [89,90]. The P-adrenoceptor antagonists have constituted the basis for more or less successful attempts to find selective 5-HTlA antagonists. Compounds 29 [91], Lilly’s 30 [92,229], and Senju’s 31 [230] are more recent examples. No anxiolytic data are available for these compounds.
Many of the classical tricyclic uptake inhibitors are potent antagonists at postsynaptic 5-HT2 receptors and down-regulate these after prolonged treatment. This effect has been suggested to be responsible for the anxiolytic effects of antidepressants [93]. Conversely, it has recently been reported that the selective and competitive 5-HT2 receptor antagonist SR 46349B up-reg- ulates 5-HT2 receptors in rat and mouse brain after chronic administration [94]. The functional interaction between 5-HT1 and 5-HT2 receptors, i.e. blockade of 5-HT2 receptors enhances 5-HT1 function, may also be relevant for the effects of 5-HT2 antagonists [95].
The close sequential relationship [96] between 5-HT2 and 5-HTlc receptor proteins has made it very difficult to design selective ligands for either of these receptors. Known selective 5-HT2 antagonists are equipotent 5-HTlc antagonists. This is the case for ritanserin (32) [97,98], which was the first ‘selective’ 5-HT2 antagonist with prominent central action that was developed as an anxiolytic. In 1985 Ceulemans et al. described the anxiolytic effects of ritanserin in man [99]. However, the role of ritanserin in the treatment of anxiety has yet to be clarified. Variable responses are obtained by testing 5-HT2 antagonists in animal models of anxiety. Generally, ritanserin is inactive in the elevated plus maze [loo] and conflict tests, except for a weak response in pigeons [35]. However, ritanserin showed some activity in the blacwwhite box in rats [ lo l l .
Recently developed 5-HT2 antagonists have shown interesting anxiolytic profiles. Rhone- Poulenc Rorer has synthesized a series of centrally acting naphthosultam 5-HT2 antagonists [102,231] of which RP 62203 (33) has been selected for further development. In accordance with the structural relationship to the 5-HT1* active phenylpiperazines described above, some 5-HTlA receptor affinity is observed with 33 [103]. In contrast to ritanserin, RP 62203 has anxiolytic properties in the elevated plus maze test [ 1001.
Sertindole (34) was developed by Lundbeck from a series of 3-(4-piperidyl)-substituted in- doles [ 104,2321 with anxiolytic properties in different animal models, e.g. the blacuwhite box in mice and rats, human threat in marmosets, and isolation-induced aggression in mice [ 105,2321. Besides being a potent, centrally acting 5-HT2 antagonist, sertindole also has affinity for D2 receptors and a1 adrenoceptors. More selective 5-HT2 antagonists with re- lated structures have recently been disclosed [233]: 6- or 2-substituted 1 -phenylindoles, 3- phenyl substituted indoles, and 5-substituted 3-phenyl-1 -piperazinylindans. No anxiolytic data were revealed for these compounds. Merrell Dow has claimed the (+)-isomer of a- (2,3-dimethoxyphenyl)- 1 -[2-(4-fluorophenyl)ethy1]-4-piperidinemethanol, MDL 100,907 (35) [234], which belongs to a previously disclosed series of 4-piperidinemethanols [235]. MDL 11,939, the analogue without substituents on the phenyl rings, was a preceding development candidate [ 1061. Interestingly, MDL 100,907 seems to be the first selective, centrally acting 5-HT2 antagonist with insignificant 5-HTlc receptor affinity [ 1073.
For several years Lilly has developed 5-HT2 antagonists within the trans-ergoline series. The isomeric mixture LY 53857 (containing four isomers) was reported as the prototype [108]; later, sergolexole (36) [ 1091 was developed and tested in man. Recent derivatives include iso- mers of N-(2- hydroxycyclopenty1)- 1 -isopropyl-6-methylergoline-8-carboxamide, LY 2 15840 [110,236]. No anxiolytic data were provided; it appears that Lilly intends these compounds to be used primarily for the treatment of cardiovascular disorders and migraine.
The role of 5-HTlc antagonism in anxiety is uncertain. It has been suggested that the induc- tion of anxiety and panic attacks in humans [111,112] after administration of the 5 - H T l ~ , c agonist/S-HTg antagonist rn-CPP is caused by its stimulation of 5-HTlc receptors [ 1131. Mixed 5-HT2/5-HTlc antagonists such as (+)-mianserin, ICI 169369 and LY 53857 enhanced social interaction within pairs of rats, while the more specific 5-HT2 antagonists, ketanserin and altanserin, had no anxiolytic profile in this test model [113]. Although no selective 5- HTlc antagonists have yet been reported, a series of indole ureas have been claimed as 5- HT1c antagonists by SmithKline Beecham [237]. The most potent compound is 37. Rather weak affinities (pKi’s 5.0-7.6) were found in 3H-mesulergine binding in pig choroid plexus membranes. Antagonism was shown by inhibition of 5-HT-induced contractions of rat stom- ach fundus. Activity for one of the compounds in a social interaction test and a conflict pro- cedure, at rather high doses (2-40 mgkg), was revealed. Further pharmacological studies are awaited for this series of compounds with quite interesting new structural features. Recently,
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CNS Agents 11 1
F
F'
n
cl&-NYNH N
\
33 RP62203
OH
I 34 sertindole 35 MDL 100,907 F
36 sergolexole 37
Lilly has claimed 5-HTlc receptor affinity of the (R)-isomer of the marketed 5-HT-uptake inhibitor, fluoxetine [238], and of the nor-metabolite [239].
5-HT3 antagonists (5-HT4 ligands)
Contrary to the 5-HT receptor subtypes discussed above, which are coupled to second mes- senger systems, 5-HT3 receptors are linked directly to ion channel functions. 5-HT3 receptors are present in cortical and limbic brain regions in rodents, and have also been shown to be present in human brain [9]. It is suggested that amygdala, but not the dorsal raphe nucleus, may represent an important neuroanatomical locus for the disinhibitory, perhaps anxiolytic, properties of 5-HT3 antagonists [114]. Although most 5-HT3 antagonists are claimed to be very selective, there are evidently some common strucrural requirements for 5-HT3 and 5-HT4 receptor interaction [ 1 15,1161.
The primary therapeutic target for 5-HT3 antagonists has been the treatment of emesis. How- ever, since the discovery that Glaxo's ondansetron (38) and other 5-HT3 antagonists have CNS activities, both related to anxiolytic and antipsychotic effects [ 117,1181, many companies have synthesized new compounds with similar activities. Relief of anxiety after withdrawal from substance abuse has also been accomplished with 5-HT3 antagonists in animal experiments
[117]. Very little information is available on the anxiolytic efficacy of these compounds in man. It has been reported in a preliminary Phase I1 study that ondansetron is effective in the treatment of GAD [ 1191. More recently disclosed 5-HT3 antagonists include Lilly’s zatosetron (39) [120], which is in clinical trials, and Wyeth’s WAY 100289 (40), which has shown an anxiolytic profile in animal models [30].
About twenty applications claiming 5-HT3 antagonists have been published during the last year; most of them are structurally related to ondansetron, the benzamide zacopride (41) [118,121], and indole, indazole, or indoline structures, e.g. BRL 46470 (42) [122,240]. Di- hydrobenzofurans (43) derived from zacopride/zatosetron have been claimed by Erbamont [241]. Anxiolytic activity was found in the social interaction and the blacMwhite box tests. Similar compounds have been disclosed by Farmitalia, but no anxiolytic data are given [242]. Thiobenzamide and 4-amidinobenzamide derivatives of zacopride, synthesized by Robins [243], showed activity in the blacWwhite box. The quinuclidine ring of zacopride has been re- placed by a 3,9-diazabicylo[3.3.1]nonan-7-y1 moiety by Beecham [244]. Again, no anxiolytic data were reported.
38 ondansetron 39 zatosetron 40 WAY 100289
41 zacopride 42 BRL46470 43
3-Quinuclidinyl or other bridged azabicylic compounds linked via amidic linkages to het- eroaromatic groups include Nippon’s 44 [245], Syntex’s 45 [246], and Novo Nordisk’s 46 [247]. Similarly, Sandoz has further developed its tropisetron in a new series of 7-alkoxy- substituted 3-indolecarboxylates [248]. Ranges of activities in social behaviour were indicated without specific data. Imidazopyridine-8-carboxamides (47) have been claimed by Searle [249]. New ondansetron derivatives from Ono include isoquinolin-1 -ones (48) [ 123,2501, and naphthothiopyranones from Taisho [25 11. Further atypical quinuclidine derivatives have been disclosed by Merck GmbH (49) [252] and Syntex (50) [253]. Compound 50 showed anxi- olytic activity in the blacWwhite box, but for a large proportion of the applications anxiolytic activity was only implicated by the mechanism of action per se, without providing test data. It is assumed that a carbonyl linkage [124] or a bioisosteric replacement group [125] between an aromatic ring and the basic nitrogen atom should be present in a 5-HT3 phannacophore. However, Wyeth has demonstrated that 5-HT3 antagonism is retained if a methylene spacer
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CNS Agents 1 13
group is present, for example, in the tropanyl derivative 51 [254]. Interestingly, the related 5-HT2 agonist quipazine has also 5-HT3 receptor affinity [124].
44 45
0
Cl
47
50
46
.“..y3yJ H
49
51
Noradrenaline (NA) According to the classical hypothesis, increased noradrenergic activity leads to overarousal and anxiety [49]. There are several indications of NA being involved in anxiety disorders. In some studies, increased levels of NA and 3-methoxy-4-hydroxyphenylglycol (MHPG) in CSF and plasma have been found in anxious patients, However, plasma NA, A (adrenaline) and MHPG levels do not significantly increase compared with control in GAD [126]. Increased synaptic availability of NA, achieved by reduction of presynaptic inhibitory function by a2- adrenoceptor antagonists such as yohimbine, NA-uptake inhibition or increased NA-release (cocaine) can induce anxiety [49]. Panic patients show increased sensitivity to a2-adrenocep- tor agonists and antagonists. Despite these theories and evidence for the involvement of the noradrenergic system, pharmaceutical companies and research institutions have not demon- strated a considerable interest in this area; very few compounds are under clinical investiga- tion and no patent applications claiming the use of such compounds as anxiolytics have been published during the last year.
Benzodiazepine (BZ)/GA BA receptor complexes Substantial evidence from electrophysiological, biochemical and behavioural studies suggests that effects of benzodiazepines are mediated by binding sites located on the GABAA receptor. This ultimately leads to an enhanced GABAergic inhibition by increasing the affinity of the
GABA receptor for GABA [49]. One theory for the mechanism of action of benzodiazepines is the existence of an endogenous ligand for the benzodiazepine receptor, i.e. anxiety dis- orders may be due to an excess of anxiogenic or a deficiency of anxiolytic substances. A further hypothesis is that the benzodiazepine receptor function is changed in anxiety disor- ders. During benzodiazepine withdrawal, enhanced effects of inverse agonists and attenuated effects of agonists are observed; antagonists become slightly inversely agonistic in their ef- fects. Furthermore, high doses of benzodiazepines are required in panic disorder, indicating a reduced sensitivity to agonist drugs.
It has been suggested that partial agonists of the benzodiazepine receptor retain full anxiolytic and anticonvulsant efficacy with reduced sedative and muscle relaxant/ataxic properties [5 11. The liability for development of tolerance and physical dependence may also be reduced in these compounds [5 11. Partial agonists at late clinical development stages include the p-car- bolin abecarnil(52, ZK 1121 19) [128] from Schering/Novo Nordisk and the Roche compound bretazenil (53, Ro 166028) [ 1291. Although abecarnil has demonstrated clinical efficacy in GAD, the presence of withdrawal symptoms [130] still leave the partial agonists to prove superiority to classic benzodiazepines. Many partial agonists are still being claimed. Lactone P-carbolines (54) have been shown by CNRS [255] to be partial BZ receptor agonists which prevented diazepam-induced sedation. New imidazo structures include Novo Nordisk’s imi- dazoquinazolines (55) [256].
0 H,C & CH, H3c) aonp \ / / \ N 0 2 CH, CH3 oNp 0 N / O N
H
A Br 0
52 abecarnil 53 bretazenil 54
Imidazopyridodiazepinones (56) from Roussel [257] act primarily as inverse BZ agonists. Imidazoquinolines and imidazopyrimidines have been studied in detail, especially by Rous- sel [ 1271. Neurogen has claimed several series of imidazo compounds for their interaction with one or more subtypes of modulatory GABAA receptors. Intrinsic activities ranged from agonists to inverse agonists. These series included imidazopyrimidines (57) [258] and im- idazoquinoxalines (58) [259]. Imidazopyrimidines closely related to 57 were also disclosed [260], as well as pyrrolopyrimidines [261]. Further partial agonists (pyrazoloquinolines) have been disclosed by Shionogi [262]. The presence of benzodiazepine receptor heterogeneity [131] has also been implicated. The development of the hypnotic zolpidem and the recently registered anxiolytic alpidem (59) from Synthdlabo [ 132,1331 was based upon interaction with subgroups of a-modulatory GABAA sites. AH Robins has claimed corresponding pyra- zoleacetamides (60) [263] and 61 [264]. Compounds were generally 10-fold less potent than diazepam in Vogel’s conflict test.
Directly acting GABA agonists and GABA-uptake inhibitors have also been proposed as anxiolytics [ 127,1341. The use of tetrahydroisoquinoline GABA autoreceptor antagonists as anxiolytics has been suggested by Wyeth [265].
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CNSAgents 11
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04 N - Pr
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59 alpidem
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57
0 4 N - P r
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60 H
58 H
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61
Excitatory amino acids (EAA) Whereas GAB Aergic function is inhibitory, the glutamatergic receptors mediate excitatory effects. Due to the colocalization of GABA receptors and glutamate receptors on the same neurones, it seems reasonable to hypothesize a role for glutamatergic receptors in anxiety.
Noncompetitive antagonists at the ion channel NMDA receptor site, such as dizocilpine (MK 801, 62) and PCP, have shown anxiolytic effects in the social interaction test [135], the elevated plus maze [135,136], and acquisition of conditioned emotional response [I 371. New compounds related to dizocilpine include Bristol-Myers Squibb’s 63 [266]. Test data for preventing neuronal damage caused by ischaemia were provided.
Competitive antagonists such as CPP and CGS 19755 (64), however, appear to give more robust effects than noncompetitive antagonists [ 1381. Nova has claimed new phosphonic acid EAA antagonists 12671 related to CGS 19755. One of the compounds, NPC 12626 (65), showed anxiolytic activity in the elevated plus-maze and in a foot-shock-induced freezing paradigm at high doses (12.5-25 mgkg). Furthermore, antipunishment effects in the Geller- Seifert procedure have been previously reported [ 1 391.
Antagonists at the strychnine-insensitive glycine binding site (coupled to NMDA recep- tors) such as HA-966, 1 -aminopropanecarboxylates or 5,7-dichlorokynurenic acid (66) also
appear to possess anxiolytic potential in some test models [6,21,140], but are inactive in others [141,142]. Indoles related to kynurenic acids have been disclosed by Merrell Dow in several applications [268]. Compound 67 is claimed to block ultrasonic vocalizations in rat pups. Novo Nordisk has shown that certain benzothienopyrazinones (68) are glycine antag- onists [269]. These are structurally related to the glycine/AMPA receptor antagonist CNQX (69). Binding data indicate that 8-F or 8-CI are optimal for high affinity. Anxiolytic potential was implicated by EAA antagonism, without further evidence provided.
H
62 dizocilpine 63 64 CGS 19755 65 NPC 12626
CI OH CI
69 CNQX 66 5,7-dichlorokynurenic acid 67 68
Peptidergic interactions Numerous neuroactive peptides have been identified in the brain. Many of these peptides af- fect behaviour in animal experiments, and some have been implicated in the psychopathology of various psychiatric disorders [ 1431.
Neuropeptide Y (NPY)
NPY is found in particularly high concentrations within limbic and cortical regions. Colocal- izations with NA, somatostatin and GABA have been demonstrated. Clinical data and data from biochemical and animal experiments suggest the involvement of NPY in depression and anxiety [143]. One hypothesis for mechanism of action of the anxiolytic effects of NPY is that an a2-adrenoceptor-mediated decrease in locus coeruleus activity is obtained [ 1431. However, this line of research is still suffering from the lack of useful synthetic compounds as tools. Another widely distributed polypeptide, which seems to play a role as a mediator of stress and anxiety, is corticotropin-releasing factor (CRF) [144,145]. The CRF system has been a target for recent anxiolytic research, for example, residue CRF peptides from The Salk Institute 12701 or nonpeptide thiopyrazoline CRF antagonists from Nova [27 11.
Cholec ys tokinin (C C K) antagonists
CCK receptors exist as CCKA and CCK, subtypes. CCKB receptors are widely distributed in the brain, e.g. in the cerebral cortex, hippocampus, nucleus accumbens, caudate-putamen and thalamus [ 146,1471. An interaction of CCK with GABAergic inhibitory neurotransmission, probably mediated through CCKB receptors, could be the neurochemical substrate for anxi-
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CNS Agents 11 7
olytic effect observed in animals [ 147,1481. Interactions with the dopaminergic system have also been described [148]. Serotonin acting through 5-HT3 receptors can release CCK from brain synaptosomes [149]. Thus, through the release of CCK activation of the serotonergic neurones could lead to activation of several possible ‘alerting systems’ involving dopamine, vasopressin, CRF and pro-opiomelanocortin [ 1481. Consequently, CCK would function as a key messenger in alerting/alarm circuits. The tetrapeptide CCK-4, which is a selective CCKB agonist, induces panic attacks both in healthy volunteers and more pronounced in panic disor- der patients [ 1501. Substantial evidence from animal studies indicates the anxiolytic potential of the selective CCKB antagonists. Key structures are L-365,260 (70) [151], which belongs to the MSD series of 1,4-benzodiazepines designed from the fungal fermentation product as- perlicin, and C1 988 (71, PD 134308) [152], which has been developed at Warner-Lambert based on rational drug design as a peptoid analogue of the CCK-4 fragment. L-365,260 was active in the blacWwhite box in mice, in a conflict procedure [150], and in the plus maze in mice [ 1531. Additionally, L-365,260 potently prevented inhibition of exploratory activity in- duced by CCK-4 [147]. C1988 has anxiolytic activity in rodents in the blacwwhite box, social interaction, elevated plus maze, and in marmosets in the human threat test [ 1461. It reversed pentagastrin-induced (CCKB agonist) anxiety in rats [ 1541. Obviously these interesting prop- erties have stimulated efforts to find new CCKB antagonists. Merck has continued with new benzodiazepine-related structures [272]. Both relief from panic and anxiety disorders have been claimed. Selectivity for brain CCKB receptors was demonstrated for several compounds, while anxiolytic activity in the blacWwhite box was reported for only one of the compounds (72). A family of C1 988 analogues has been claimed by Warner-Lambert [273]. Some of the more interesting changes were either replacement of the indole ring in 71 with other aryl groups ( e g benzofuran) or the indole was further condensed into a tetrahydro-P-carboline. Binding affinities for CCKB receptors and anxiolytic effects in the elevated plus maze and the blacuwhite box were given for a few of these new compounds. Rhone-Poulenc has developed ureido-acetamides (73) related to proglumide [ 155,2741. Also, Lilly has identified a preclini- cal development candidate, LY 262691 (74) [156,275]. Pfizer [276], Yamanouchi [277] and James Black Ltd [278] all have recent patent applications claiming CCKB antagonists. Only binding affinities were provided by these companies.
Miscellaneous Even though the functional role of o-binding sites in states of anxiety remains unclear, dif- ferent o-ligands can cause both anxiogenic and anxiolytic effects. (+)-Pentazocine, which is a selective ligand for the proposed ol-binding site [157], produces anxiety in humans [158] and fear in Vogel’s conflict test [159]. Recently, the University of Oregon has claimed a se- ries of guanidines (75) [ 160,2791 related to the o-ligand ditoluylguanidine (DTG). Nanomolar affinity for o-receptors was shown in a binding assay using 3H-DTG. The guanidines were nonsedative with prominent anxiolytic effects in the blacWwhite box (mice) and social inter- action test (rats). Within another series of selective o-active spiroisobenzofurans, compound 76 showed a potent anxiolytic profile in the blacWwhite box in rats [161].
Anecdotal reports from the clinic speculate that ACE inhibitors induce a feeling of well being in hypertensive patients and that depressive symptoms are relieved [ 162,1631. ACE inhibitors have shown anxiolytic effects in some animal models [161]. Squibb has claimed the use of an ACE inhibitor, ceranapril, in combination with the 5-HT3 antagonist zacopride [280]. A related target is angiotensin I1 antagonists of which several are claimed to have anxiolytic action, as well as other CNS effects. Merck has been most progressively pursuing this strategy [28 11. Anxiolytic effect was indicated in a conditioned emotional response (CER) assay, but no specific biological data were provided.
It has been suggested that several clinically active drugs, including benzodiazepines and barbi- turates, may exert some of their actions by affecting endogenous adenosine levels in the brain [ 1641. The adenosine agonist I-PIA reverses the anticonflict effect of phenobarbital. Benzodi- azepines potentiate the action of adenosine by mean of uptake inhibitory effects [ 1651. Merrell Dow has claimed new xanthine derivatives as adenosine A-1 and A-2 agents [282] . Anxiety
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CNS Agents 1 19
was claimed as a potential therapeutic application, but only receptor binding affinities were provided.
Conclusion
Interesting prospects for successors to benzodiazepines have appeared from recent years’ re- search. A variety of mechanistic approaches seem possible as many classes of compounds show anxiolytic effects in animal models. The groups of compounds in the most advanced stages of development are partial 5-HTlA agonists, 5-HT3 antagonists, 5-HT-uptake in- hibitors, and CCKB antagonists. In contrast to benzodiazepines, new nonbenzodiazepine com- pounds are generally active only in some animal models and responses are often less consis- tent. Whether this reflects the complexity of anxiety disorders in man or a lack of predictability of some of the animal models still remains to be solved by carefully conducted and controlled clinical investigations. The new mechanisms of action are likely to attract increased attention from clinicians to subtypes of anxiety disorders and neurochemical mechanisms underlying different anxiety symptoms. Several serotonergic compounds will undoubtedly reach the mar- ket within the next five years, probably not as a complete replacement for the benzodiazepines, but with specific applications according to their individual anxiolytic properties. This is al- ready the case for buspirone which is recommended as a replacement for benzodiazepines in long-term treatment of GAD due to its lack of immediate efficacy and of dependence liability. 5-HT-uptake inhibitors and possibly also CCKB antagonists appear to be likely candidates for the treatment of PD. The major challenge for a successful replacement of the benzodiazepi- nes involves maintaining their rapid onset of action and avoiding their side-effect liability. Generally, such aspects are not disclosed in patent applications. Consequently more relevant data for recently claimed compounds are needed to fully evaluate the prospects for these compounds.
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