¹Department of Screening and Compound Profiling, Molecular Discovery Research, GlaxoSmithKline, Essex, UK

Correspondence: Dr AJ Brown, Department of Screening and Compound Profiling, Molecular Discovery Research, GlaxoSmithKline, H35L3 New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK. E-mail: andrew.j.brown@gsk.com

Received 22 June 2007; Revised 28 August 2007; Accepted 28 August 2007; Published online 1 October 2007.

Abstract

Cannabinoids have numerous physiological effects. In the years since the molecular identification of the G protein-coupled receptors CB₁ and CB₂, the ion channel TRPV₁, and their corresponding endogenous ligand systems, many cannabinoid-evoked actions have been shown conclusively to be mediated by one of these specific receptor targets. However, there remain several examples where these classical cannabinoid receptors do not explain observed pharmacology. Studies using mice genetically deleted for the known receptors have confirmed the existence of additional targets, which have come to be known collectively as non-CB₁/CB₂ receptors. Despite intense research efforts, the molecular identity of these non-CB₁/CB₂ receptors remains for the most part unclear. Two orphan G protein-coupled receptors have recently been implicated as novel cannabinoid receptors; these are GPR119, which has been proposed as a receptor for oleoylethanolamide, and GPR55 which has been proposed as a receptor activated by multiple different cannabinoid ligands. In this review I will present an introduction to non-CB₁/CB₂ pharmacology, summarize information on GPR55 and GPR119 currently available, and consider their phylogenetic origin and what aspects of non-CB₁/CB₂ pharmacology, if any, they help explain.