Manik Reddy Pullagurla

N1-Benzenesulfonylgramine and N1-benzenesulfonylskatole: novel 5-HT6 receptor ligand templates

1-Benzenesulfonyl-5-methoxy-N,N-dimethyltryptamine (3; K(i)=2.3 nM) is a 5-HT(6) receptor antagonist; removal of the 5-methoxy group (i.e., 6; K(i)=4.1 nM) has little impact on receptor affinity. In the present study, it is shown that the aminomethyl portion of 6 can be shortened to gramine analogue 10a (K(i)=3.1 nM); a related skatole derivative 11b (K(i)=12 nM) also binds with high affinity indicating that the aminoethyl portion of the tryptamines is not required for binding. Compounds 10a and 11b represent members of novel classes of 5-HT(6) antagonists.

Stimulus effects of three sulfur-containing psychoactive agents.

Two agents gaining popularity on the illicit drug market are the phenylalkylamines 4-MTA and 2C-T-7 [or 1-(4-methylthiophenyl)-2-aminopropane and 2-(2,5-dimethoxy-4-n-propylthiophenyl)-1-aminoethane, respectively]. At this time, there exists a paucity of information on the behavioral actions of these sulfur-containing agents. The present investigation examined these agents, and the N-monomethyl analog of 4-MTA (i.e., 4-MTMA), in tests of stimulus generalization (substitution) using a two-lever drug discrimination task with groups of rats trained to discriminate either the hallucinogen DOM [1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane], the stimulant cocaine, or the empathogen MDMA from vehicle. 4-MTA and its N-monomethyl analog 4-MTMA (ED50 = 0.8 mg/kg in both cases) substituted only for the MDMA stimulus, whereas 2C-T-7 (ED50 = 0.8 mg/kg) substituted only for the DOM stimulus. Thus, at the doses examined, 4-MTA and 4-MTMA appear to be MDMA-like agents, and 2C-T-7 seems best classified as a DOM-like hallucinogen. These results provide additional data that extend the structure-activity relationships of phenylalkylamines and that are consistent with what little is currently known about the action of 4-MTA and 2C-T-7 in humans.

5-ZATRYPTAMINE ANALOGS AS h5-HT6 SEROTONIN RECEPTOR LIGANDS

Abstract5-Aza analogs were prepared of several tryptamine derivatives and a skatole derivative known to bind at human 5-HT6 receptors and evaluated to determine if they bind in a manner similar to their indolic analogs. In general, the azatryptamines did not behave exactly like their tryptamine counterparts, but the behavior of N1-benzenesulfonyl analogs was reminiscent of the known arylsulfonyltryptamines. For example, N1-(4-aminobenzenesulfonyl)-5-azaskatole (18; Ki = 41 nM) displayed an affinity comparable to N1-(4-aminobenzenesulfonyl)skatole.