Selective potentiation of noradrenaline in the guinea-pig vas deferens by 2-(4-methylaminobutoxy) diphenylmethane hydrochloride (MCI-2016), a new psychotropic drug.

In the isolated vas deferens of the guinea-pig, the effects of 2-(4-methylaminobutoxy) diphenylmethane hydrochloride (MCI-2016), a new psychotropic drug, on the contractile response to various agonists or transmural electrical stimulation and on the release of noradrenaline (NA) from the tissue were examined and compared with cocaine. MCI-2016 (3 X 10(-6)M) and cocaine (3 X 10(-5)M) produced a leftward shift (15 and 20 times, respectively) of the dose-response curves for the contractile effect of NA and increased the maximum contractile response to NA by approximately 7 and 14% respectively. MCI-2016 had no apparent effect on the dose-response curves for methoxamine, acetylcholine and high K, while cocaine markedly shifted those for these agents to the left and increased the maximal responses (10, 16 and 16%, respectively). MCI-2016 and cocaine abolished the tyramine (3 X 10(-4)M)-induced contraction and inhibited the twitch response to transmural electrical stimulation in a dose-dependent manner. The inhibitory effects of both drugs on the twitch were reversed by yohimbine (10(-5)M). The spontaneous outflow of NA from the vas deferens was unaffected by MCI-2016 (3 X 10(-6)M) and cocaine (10(-5)M), while the high-K-evoked release of NA was increased by both drugs. In the presence of cocaine (10(-5)M), the high-K-evoked release of NA was markedly increased by yohimbine (10(-5)M) and decreased by clonidine (3 X 10(-8)M), but only slightly increased by MCI-2016 (3 X 10(-6)M). 7 In phaeochromocytoma cells, both MCI-2016 and cocaine at concentrations of 10-7 to 10-5 M caused a dose-dependent inhibition of the [3H]-NA uptake. 8 These results suggest that MCI-2016-induced supersensitivity is specific for NA and is due to interference with the neuronal uptake process for NA.