Influence of the N-1 alkyl chain length of cannabimimetic indoles upon CB1and CB2 receptor binding

The N-1 alkyl side chain of the aminoalkylindole analogues (AAI) has been i mplicated as one of a three-point interaction with the cannabinoid CB1 rece ptor. In this study, the morpholinoethyl of WIN 55,212-2 was replaced with carbon chains of varying lengths ranging from a methyl to heptyl group. Add itional groups were added to the naphthoyl and the C2 positions of the mole cule. These structural changes revealed that high affinity binding to the C B1 and CB2 receptors requires an alkyl chain length of at least three carbo ns with optimum binding to both receptors occurring with a five carbon side chain. An alkyl chain of 3-6 carbons is sufficient for high affinity bindi ng; however, extension of the chain to a heptyl group results in a dramatic decrease in binding at both receptors. The unique structure of the cannabi mimetic indoles provides a useful tool to define the ligand-receptor intera ction at both cannabinoid receptors and to refine proposed pharmacophore mo dels. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.