CHEMISTRY & BIODIVERSITY – Vol. 4 (2007) 1707 REVIEW Medicinal Chemistry Endeavors around the Phytocannabinoids by Eric Stern and Didier M. Lambert* Drug Design and Discovery Center and Unite´ de Chimie pharmaceutique et de Radiopharmacie, Ecole de Pharmacie, Faculte´ de Me´decine, Universite´ catholique de Louvain, Avenue E. Mounier 73, U.C.L. 73.40, B-1200 Bruxelles (phone: þ3227647347; fax: þ3227647363; e-mail:
[email protected]) Over the past 50 years, a considerable research in medicinal chemistry has been carried out around the natural constituents of Cannabis sativa L. Following the identification of D9-tetrahydrocannabinol (D9-THC) in 1964, critical chemical modifications, e.g., variation of the side chain at C(3) and the opening of the tricyclic scaffold, have led to the characterization of potent and cannabinoid receptor subtype-selective ligands. Those ligands that demonstrate high affinity for the cannabinoid receptors and good biological efficacy are still used as powerful pharmacological tools. This review summarizes past as well as recent developments in the structure–activity relationships of phytocannabinoids. 1. Introduction. – Despite the wide uses of preparations of the hemp Cannabis sativa L. during the History, the modern pharmacology of natural cannabinoids has been hampered by the slow progress in the elucidations of the chemical structures of its major components. Indeed, it is nowadays known that more than 70 compounds derived from a diterpene structure are present in the plant [1], and this fact may explain the difficulty to obtain pure chemical entities in the past. In addition, the medicinal research for more than a half century has been driven by the search for the components responsible for the psychoactive effects of cannabis, this era in the history of the chemical research on cannabinoids have been recently reviewed [2][3].