Aminoalkylindoles: actions on specific G-protein-linked receptors

Abstract

Aminoalkylindoles (AAIs) are antinociceptive agents which act through two distinct mechanisms: inhibition of cyclooxygenase and a novel mechanism retained by AAI analogs which do not inhibit cyclooxygenase. This latter mechanism is reflected by inhibition of neuronally mediated contractions in several smooth muscle bioassays. The present studies explored the potential receptor interactions of AAIs in smooth muscle preparations and in rat brain membranes. Experiments in an electrically stimulated mouse vas deferens preparation (MVD) demonstrated that several AAI agonists inhibited neuronally mediated muscle contractions over a wide potency range (0.1-1000 nM) and in a stereospecific manner. Also, a putative AAI antagonist analog selectively attenuated AAI-induced inhibition in the MVD: 10 microM of the antagonist analog produced 16- to 40-fold rightward shifts in the concentration-effect curves for AAI agonists but failed to attenuate the inhibitory actions of several receptor agonists and other pharmacological agents. AAI agonists also inhibited adenylyl cyclase in membranes from rat striatum and cerebellum. AAI agonists inhibited adenylyl cyclase through G-proteins, because AAI-inhibited adenylyl cyclase required GTP, and was not supported by nonhydrolyzable guanine nucleotides. Inhibition of adenylyl cyclase by several AAI agonists was stereospecific and was not blocked by antagonists of several traditional neurotransmitter receptors. The potencies of AAI agonists to inhibit cerebellar adenylyl cyclase were highly correlated (r = 0.97) with their potencies to inhibit contractions of MVD. These results suggest that AAIs bind to specific receptors which are coupled through G-proteins to inhibit adenylyl cyclase.