Structure and receptor activity for classical cannabinoids.

Abstract

In this decade, classical cannabinoid SAR has increasingly been interpreted in terms of ligand-receptor interaction. Membrane receptor binding affinity, inhibition of receptor coupled processes, functional in vitro assays that distinguish between agonists and antagonists, transfected receptor systems, and distinction among receptor subtypes have been applied to cannabinoid pharmacology studies. These studies have revealed information about the pivotal receptor interaction that mediates the neurochemical system characterized by the receptor. The positive correlation between binding affinity and behavioral effects validates ligand-receptor interaction as a focus for developing new cannabinoids with the potential for selective pharmacological effects. Added to these direct receptor studies are the computational methods that compare active and inactive ligands for steric, electronic, and conformational similarities that reveal an SAR for activity with a sophistication and a perspective not possible before computer methodology. Merging these studies with knowledge of the receptor sequence, consequences of mutations of the receptor, and a calculated structure of the receptor are evolving a physical picture of the interaction of cannabinoids with its receptor(s). This picture of a ligand-receptor interaction guides medicinal chemists in their interpretation of classical cannabinoid SAR and the design of new analogs for selective pharmacological activity and as probes of the cannabinoid receptor. It is from a receptor perspective that this review of the SAR of classical cannabinoids is presented.