Effects of semirigid methoxamine analogs on vascular smooth muscle: studies of methoxy-2-aminotetralin and 2-aminoindane derivatives.

The effects of semirigid methoxy analogs of 2-aminotetralin (2-AT) and 2-aminoindane (2-AI) were studied on superfused dog metatarsal veins to investigate postjunctional interactions produced by these agents on sympathetically innervated vascular smooth muscle. The following compounds were tested: norepinephrine (NE); serotonin (5-HT); amphetamine (AMP); methoxamine (MTH); 2-di-n-propylamino-4,7-dimethoxyindane (RDS-127); 2-di-n-propylamino-5,6,-dimethoxyindane (JPC-211); 2-di-n-propylaminoindane (JPC-6036); 2-methylamino-5,8-dimethoxytetralin (DR-31); 2-methylamino-4,7-dimethoxyindane (RDS-31). The results of this study indicate that contractions produced by these compounds have the following ranked ordered potencies: 5-HT greater than NE much greater than MTH greater than or equal to RDS-127 = DR-31; JPC-6036, RDS-31, JPC-211 and AMP were inactive. The contractions produced by NE, MTH, RDS-127 or DR-31, but not 5-HT, probably occur through alpha1-adrenergic receptors since these contractions were blocked with prazosin. 5-HT and RDS-127, but not NE, MTH or DR-31 activate serotonin receptors since methysergide blocked the response produced by 5-HT or RDS-127. NE-induced contractions were augmented and tyramine-induced contractions were attenuated with cocaine. The responses of MTH, RDS-127 or DR-31 probably do not displace NE through a tyramine-like action since cocaine had no effect on contractions induced by these compounds. These data suggest that semirigid paramethoxylated derivatives of 2-AT and 2-AI are potent postjunctional receptor agonists which probably initiate venoconstriction via direct receptor interactions. The structure-activity relationships of these compounds are discussed.