T. Rogosch a*, P. Imming a, M. Kathmann b
a Institut für Pharmazeutische Chemie, Universität Marburg, Germanyb Institut für Pharmakologie u. Toxikologie, Universität Bonn, Germany
Arylpropionic and arylacetic
acid derivatives as analogs of
endogenous cannabinoids
Cannabinoids
• structure elucidation of ∆9-THC in 1964
• first evidence for the existence of specificbinding sites for canabinoids in 1988
O
OH
∆9-tetrahydrocannabinol
Endogenous cannabinoid system
• two subtypes, CB1 and CB2
• CB1 receptors are located in the CNS,predominantly on interneurons in regions formotor function, pain and learning
• CB2 receptors are located in the peripheral nervousand immune system, e.g. on mast cells, B- and T-lymphocytes
• endogenous ligands are anandamide,2- arachidonylglycerol and noladinether
Cannabinoid receptors
• CB1 receptors:
Central nervous system, areas responsible forcognition, short-term memory, motor function, pain
• CB2 receptors:
immune system, mast cells and B- and T-lymphocytes
Both receptors are coupled through Gi/o proteins
Inactivation system
NH
OHO
OH
O
NH2OH
FAAH+
• uptake of anandamide
• intracellular degradation, catalysed by FAAH
Endogenous cannabinoid system
takes part in:
antinociception, brain development, control of motorfunction, immune regulation, cell proliferation
compounds influencing the ECS are potentialtherapeutics for treatment of pain or neurodegenerativediseases like multiple sklerosis
Ki [nM] of endogenous ligands
145>3000371CB2
58.321.289CB1
2-ArachidonylglycerolNoladinetherAnandamide
NH
OHO
Anandamide
O
O
OH
OH
2-Arachidonylglycerol
OOH
OH
Noladinether
COX inhibitors
• only S-enantiomers inhibit COX
• R-enantiomers also have analgetic potency
• mimic arachidonic acid
OH
O
Ibuprofen
*
OH
OO
Naproxen
*F
OH
O
Flurbiprofen
*
N
O
O
OH
O Cl
Indometacin
Arylpropionic acids interact with theendogenous cannabinoid system
• Ibuprofen and flurbiprofen inhibit the hydrolysis ofanandamide at pharmacologically relevantconcentrations
• R-(-)-Ibuprofen is about 2-3 times more potent thanthe S-(+)-enantiomer
• co-injection of PGE2 hardly affects analgesia, butAM-251 (selective CB1 inhibitor) suppresses it
Synthesis of ethanolamides
OHR
O
OHF
F
FF
F
OF
F
FF
F
R
O
OH
NH2 NH
R
OOH+
+ DCC
in EtOAc
+
in CHCl3
• reactivity of pentafluorophenyl esters towardsN- nucleophiles comparable to acid chlorides, butmuch more stable towards O-nucleophiles
• purification via flash chromatography
Synthesised arylacetic andarylpropionic acid derivatives
N
O
O
NH
O Cl
OH
F
NH
OOH*
NH
OOH*
NH
OO
OH*
Affinity of ethanolamides towardsCB1 receptors
• CB1 receptors were extracted from the cerebralcortex of male rats
• incubation with [3H]-SR 141716
• determination of residualradioactivity N
N
NH
O N
Cl Cl
Cl
Affinity of ethanolamides towardsCB1 receptors
-10 -9 -8 -7 -6 -5
0
50
100TR 04
TR 08TR 10
TR 02
TR 06
TR 12TR 14SR 141716
Drug (log M)
Spec
ific
3 H-S
R 1
4171
6bi
ndin
g (%
of c
ontr
ols)
Affinity of ethanolamides towardsCB1 receptors
• recent studies suggest that there are two bindingregions for cannabinoids at CB1( McAllister et al. J.Med.Chem 2003, 46, 5139 )
• one for aminoalkylindols and diaryl pyrazoles likeSR 141716
• one for endogenous ligands like anandamide andnonclassical agonists
Affinity of ethanolamides towardsCB1 receptors
-10 -9 -8 -7 -6 -5
0
50
100TR 04
TR 08TR 10
TR 02
TR 06
TR 12TR 14SR 141716Anandamid
Drug (log M)
Spec
ific
bind
ing
(% o
f con
trol
s)
Summary
• mechanism of analgetic potency of R-enantiomersunknown yet
• possible interaction with cannabinoid system
• no affinity towards CB1 receptors of synthesisedethanolamides
Outlook
• CB2 receptors (less demanding concerningsubstrate geometry)
• FAAH (fatty acid amidohydrolase)
• VR1 receptors (vanilloid receptors)
synthesis of other metabolites e.g. symmetricglycerol esters
possible affinity towards following targets - to betested: