Characterization of a novel and potent 5-hydroxytryptamine 1A receptor antagonist

Abstract

A series of pindolol derivatives (n = 7) was analyzed in radioligand binding, biochemical and behavioral studies. Three of these drugs (Compounds A, B, and C) are extremely potent (i.e., K i values <1.0 nM) at 5-hydroxytryptamine 1A (5-HT 1A) sites labeled by [ 3H] 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT). Moreover, these drugs are selective in that they are approximately an order of magnitude less potent at beta-adrenergic receptors labeled by 3H-dihydroalprenolol (DHA). Compound A (N 1-(bromoacetyl)-N 8-[3-(4-indolyloxy)-2-hydroxypropyl]-(Z)-1,8-diamino-p-methane) is also significantly less potent at 10 other neurotransmitter receptor sites analyzed. In addition, Compound A (10 −10 M to 10 −3 M) has no effect on baseline forskolin-stimulated adenylate cyclase activity in rat hippocampus. By contrast, nanomolar concentrations of the drug significantly ( p<0.01) reverse 8-OH-DPAT-induced inhibition of forskolin-stimulated activity. In behavioral studies, Compound A (0.5 mg/kg) alone has no effect on baseline measures of reciprocal forepaw treading in the rat. Pretreatment with Compound A, however, significantly ( p<0.05) inhibits the reciprocal forepaw treading induced by 8-OH-DPAT. These data suggest that Compound A is a potent and selective antagonist of 5-HT 1A receptors in the CNS.