Characterization of a novel and potent 5-hydroxytryptamine1A receptor antagonist.

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., Ki values less than 1.0 nM) at 5-hydroxytryptamine1A (5-HT1A) 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 (N1-(bromoacetyl)-N8-[3-(4-indolyloxy)-2-hydroxypropyl]-(Z)-1,8-di amino-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 cycalse activity in rat hippocampus. By contrast, nanomolar concentrations of the drug significantly (p less than 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 less than 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-HT1A receptors in the CNS.