1-Pentyl-3-phenylacetylindoles, a new class of cannabimimetic indoles

A new class of cannabimimetic indoles, with 3-phenylacetyl or substituted 3-phenylacetyl substituents, has been prepared and their affinities for the cannabinoid CB1 and CB2 receptors have been determined. In general those compounds with a 2-substituted phenylacetyl group have good affinity for both receptors. The 4-substituted analogs have little affinity for either receptor, while the 3-substituted compounds are intermediate in their affinities. Two of these compounds, 1-pentyl-3-(2-methylphenylacetyl)indole (JWH-251) and 1-pentyl-3-(3-methoxyphenylacetyl)indole (JWH-302), have 5-fold selectivity for the CB1 receptor with modest affinity for the CB2 receptor. GTPγS determinations indicate that both compounds are highly efficacious agonists at the CB1 receptor and partial agonists at the CB2 receptor.

Graphical abstractThe synthesis and pharmacology of 30 1-pentyl-3-arylacetylindoles (R = H and CH3) are described. Two of these compounds are highly efficacious and selective ligands for the CB1 receptor.Figure optionsDownload full-size imageDownload as PowerPoint slide