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., K(i) values < 1.0 nM) at 5-hydroxytryptamine1A (5-HT1A) sites labeled by [H-3] 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 H-3-dihydroalprenolol (DHA). Compound A (N1-(bromoacetyl)-N8-[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-HT1A receptors in the CNS.