Pharmacological characterization of (10bS)-1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]isoquinoline oxalate (YSL-3S) as a new alpha(2)-adrenoceptor antagonist

alpha(2)-Adrenoceptor antagonists, which can enhance synaptic norepinephrin e levels by blocking feedback inhibition processes, are potentially useful in the treatment of disease states such as depression, memory impairment, i mpotence and sexual dysfunction. (10bS)-1,2,3,5,6,10b-Hexahydropyrrolo[2,1- a]isoquinoline oxalate (YSL-3S) was evaluated in several in vitro biologica l tests to establish its pharmacological profile of activities as an alpha( 2)-adrenoceptor antagonist. Saturation binding assay revealed that [H-3]rau wolscine bound to the alpha(2)-adrenoceptors with a Kd value of 6.3 +/- 0.5 nM and a Bmax value of 251 +/- 39 fmol/mg protein in rat cortical synaptic membranes. Competitive binding assay showed that YSL-3S inhibited the bind ing of [H-3]rauwolscine (1 nM) in a concentration-dependent manner with a K i value of 98.2 +/- 12.1 nM while it did not inhibit the binding of [H-3]cy tisine (1.25 nM) to neuronal nicotinic cholinergic receptors. The Ki values of yohimbine, clonidine and norepinephrine for [H-3]rauwolscine binding we re 15.8 +/- 1.0, 40.1 +/- 5.9 and 40.0 +/- 11.5 nM, respectively. In additi on, the binding affinity of YSL-3S for a(2)-adrenoceptors was higher than t hat of its antipode and the racemic mixture. The functional activity of YSL -3S at the presynaptic alpha(2)-adrenoceptors was assessed using the prosta tic portion of the rat vas deferens. Clonidine inhibited field-stimulated c ontractions of the vas deference in a dose-dependent manner. The presence o f YSL-3S or yohimbine caused a parallel, rightward the dose-response curve of clonidine in a dose-dependent manner, indicating an antagonistic action at the presynaptic alpha(2)-adrenoceptors. The pA(2) values of yohimbine an d YSL-3S were 7.66 +/- 0.13 and 6.64 +/- 0.18, respectively. The results in dicate that YSL-3S acts as a competitive antagonist at presynaptic alpha(2) -adrenoceptors with a potency approximately ten times lower than yohimbine, but is devoid of binding affinity for neuronal nicotinic cholinergic recep tors.