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: