Research Paper
Subject Category: Neuropharmacology
British Journal of Pharmacology (2007) 152, 805–814; doi:10.1038/sj.bjp.0707347; published online 25 June 2007
PSNCBAM-1, a novel allosteric antagonist at cannabinoid CB1 receptors with hypophagic effects in rats
J G Horswill1, U Bali1, S Shaaban1,2, J F Keily1, P Jeevaratnam1, A J Babbs1, C Reynet1 and P Wong Kai In1
1Prosidion Limited, Windrush Court, Oxford, UK
Correspondence: P Wong Kai In, Prosidion Limited, Windrush Court, Watlington Road, Oxford, OX4 6LT, UK. E-mail: pwong-kai-in@prosidion.com
2Current address: OSI Pharmaceuticals Inc., 1 Bioscience Park Drive, Farmingdale, NY 11735, USA.
Prosidion Limited is a wholly owned subsidiary of OSI Pharmaceuticals Inc.
Received 7 March 2007; Revised 25 April 2007; Accepted 3 May 2007; Published online 25 June 2007.
Abstract
Background and purpose:
Rimonabant (AcompliaTM, SR141716A), a cannabinoid CB1 receptor inverse agonist, has recently been approved for the treatment of obesity. There are, however, concerns regarding its side effect profile. Developing a CB1 antagonist with a different pharmacological mechanism may lead to a safer alternative. To this end we have screened a proprietary small molecule library and have discovered a novel class of allosteric antagonist at CB1 receptors. Herein, we have characterized an optimized prototypical molecule, PSNCBAM-1, and its hypophagic effects in vivo.
Experimental approach:
A CB1 yeast reporter assay was used as a primary screen. PSNCBAM-1 was additionally characterized in [35S]-GTP
S, cAMP and radioligand binding assays. An acute rat feeding model was used to evaluate its effects on food intake and body weight in vivo.
Key results:
In CB1 receptor yeast reporter assays, PSNCBAM-1 blocked the effects induced by agonists such as CP55,940, WIN55212-2, anandamide (AEA) or 2-arachidonoyl glycerol (2-AG). The antagonist characteristics of PSNCBAM-1 were confirmed in [35S]-GTPS binding and cAMP assays and was shown to be non-competitive by Schild analyses. PSNCBAM-1 did not affect CB2 receptors. In radioligand binding assays, PSNCBAM-1 increased the binding of [3H]CP55,940 despite its antagonist effects. In an acute rat feeding model, PSNCBAM-1 decreased food intake and body weight.
Conclusions and implications:
PSNCBAM-1 exerted its effects through selective allosteric modulation of the CB1 receptor. The acute effects on food intake and body weight induced in rats provide a first report of in vivo activity for an allosteric CB1 receptor antagonist.
Keywords:
allosteric modulator, cannabinoid receptor, antagonist
Abbreviations:
2-AG, 2-arachidonoyl glycerol; AEA, arachidonoyl ethanolamide; AM630, (6-Iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl)(4-methoxyphenyl) methanone; CP55, 950 (-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl) cyclohexanol; DPCPX, 8-cyclopentyl-1,3-dipropylxanthine; hCB1, human cannabinoid receptor 1; hCB2, human cannabinoid receptor 2; HEK, human embryonic kidney; IBMX, 3-isobytyl-1-methylxanthine; PSNCBAM-1, 1-(4-chlorophenyl)-3-[3-(6-pyrrolidin-1-ylpyridin-2-yl)phenyl]urea; SR141716A, N-(piperidin-1-yl)-5-(4-cholrophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide; WIN55,212-2, R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]-pyrrolo[1,2,3,-de]-1,4-benzoxazinyl]-(1-naphthalenyl) methanone mesylate
