Derivatives of 4-(2-N,N-Di-n-propylaminoethyl)-5-hydroxyindole: Synthesis and Pharmacological Effects
Abstract5-Methoxy-l-methyl-4-(2-N,N-di-n-propylaminoethyl)indole (12) was synthesized from 5-hydroxyindole by a multistep synthesis. This target compound was designed as a bioisostere of “p-dimethoxy” catechol congeners of dopaminergic agonists derived from a variety of ring systems, in some of which p-dimethoxy-substituted systems are potent, active dopaminergic agonists. To complete the indole series, all possible combinations of N- and O-demethylated derivatives of 12 were prepared and were also evaluated pharmacologically. All members of this indole-derived series showed a low order of cardiovascular activity, which appeared to be independent of dopamine receptors. The lack of dopaminergic activity of 12 is cited as yet another example of the unpredictable effect of replacement of the catechol moiety of a dopaminergic agonist with a p-dimethoxy moiety.
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.
Highly enantio- and diastereoselective synthesis of β-methyl-γ-monofluoromethyl-substituted alcohols.
Enanatiopure β-methyl-γ-monofluoromethyl alcohols were prepared from the allylic alkylation between fluorobis(phenylsulfonyl)methane with Morita-Baylis-Hillman carbonates. The reaction was catalyzed by using the Cinchona alkaloid derivative, (DHQD)(2)AQN. The origin of the stereoselectivity was verified by DFT methods. Calculated geometries and relative energies of various transition states strongly support the observed stereoselectivity.