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PSNCBAM-1, a novel allosteric antagonist at cannabinoid CB1 receptors with hypophagic effects in rats.
Br J Pharmacol. 2007 Nov; 152(5):805-14.BJ

Abstract

BACKGROUND AND PURPOSE

Rimonabant (Acomplia, 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]-GTPgammaS, 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]-GTPgammaS 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.

Authors+Show Affiliations

Prosidion Limited, Windrush Court, Oxford, UK.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

17592509

Citation

Horswill, J G., et al. "PSNCBAM-1, a Novel Allosteric Antagonist at Cannabinoid CB1 Receptors With Hypophagic Effects in Rats." British Journal of Pharmacology, vol. 152, no. 5, 2007, pp. 805-14.
Horswill JG, Bali U, Shaaban S, et al. PSNCBAM-1, a novel allosteric antagonist at cannabinoid CB1 receptors with hypophagic effects in rats. Br J Pharmacol. 2007;152(5):805-14.
Horswill, J. G., Bali, U., Shaaban, S., Keily, J. F., Jeevaratnam, P., Babbs, A. J., Reynet, C., & Wong Kai In, P. (2007). PSNCBAM-1, a novel allosteric antagonist at cannabinoid CB1 receptors with hypophagic effects in rats. British Journal of Pharmacology, 152(5), 805-14.
Horswill JG, et al. PSNCBAM-1, a Novel Allosteric Antagonist at Cannabinoid CB1 Receptors With Hypophagic Effects in Rats. Br J Pharmacol. 2007;152(5):805-14. PubMed PMID: 17592509.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - PSNCBAM-1, a novel allosteric antagonist at cannabinoid CB1 receptors with hypophagic effects in rats. AU - Horswill,J G, AU - Bali,U, AU - Shaaban,S, AU - Keily,J F, AU - Jeevaratnam,P, AU - Babbs,A J, AU - Reynet,C, AU - Wong Kai In,P, Y1 - 2007/06/25/ PY - 2007/6/27/pubmed PY - 2008/2/26/medline PY - 2007/6/27/entrez SP - 805 EP - 14 JF - British journal of pharmacology JO - Br J Pharmacol VL - 152 IS - 5 N2 - BACKGROUND AND PURPOSE: Rimonabant (Acomplia, 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]-GTPgammaS, 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]-GTPgammaS 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. SN - 0007-1188 UR - https://www.unboundmedicine.com/medline/citation/17592509/PSNCBAM_1_a_novel_allosteric_antagonist_at_cannabinoid_CB1_receptors_with_hypophagic_effects_in_rats_ L2 - https://doi.org/10.1038/sj.bjp.0707347 DB - PRIME DP - Unbound Medicine ER -