Indolealkylamine analogs share 5-HT2 binding characteristics with phenylalkylamine hallucinogens.
Twenty-one indolealkylamines, some of which are known to be psychoactive in man, were examined for their binding interactions with rat brain cortical 5-HT2 receptors labeled with the antagonist radioligand [3H]ketanserin in order to develop structure-activity relationships for binding at these sites. Features investigated included aromatic, alpha-methyl and terminal amine substituents. 4-Methoxy and 5-methoxy substitution impart a higher affinity than 6- or 7-methoxy substitution; a 7-hydroxyl group essentially abolishes affinity whereas a 7-methyl or 7-bromo group enhances affinity. alpha-Methylation has little effect on affinity and, in the one case examined, the S(+) isomer of alpha-methyltryptamine was essentially equipotent with its racemate and twice as potent as its R(-) enantiomer. Terminal amine methylation results in a small but progressive decrease in affinity in the order: primary amine greater than dimethylamine greater than diethylamine. Similarities were noted between these structural requirements for binding and those of the phenalkylamines. Selected compounds (5-methoxytryptamine, N,N-dimethyltryptamine, 5-methoxy-N,N-diethyltryptamine and 5-methoxy-N,N-dimethyltryptamine) were further examined by two-site analysis of displacement studies for [3H]ketanserin specific binding. Hill coefficients were significantly less than unity and computer-assisted analysis indicated that a two-site model better fit the data than a one-site model. In displacement studies using the putative agonist radioligand [3H]DOB to label 5-HT2 receptors affinities were 10-100-fold higher than those using [3H]ketanserin. These results are also consistent with earlier findings using psychoactive phenalkylamines in competition studies for radiolabelled 5-HT2 receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
Lyon
R A
RA
Department of Pharmacology and Toxicology, Albany Medical College, NY 12208.
Titeler
M
M
Seggel
M R
MR
Glennon
R A
RA
D004290:DOM 2,5-Dimethoxy-4-Methylamphetamine / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D000588:Amines / Q000378:metabolism*; D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism; D003198:Computer Simulation; D006213:Hallucinogens / Q000378:metabolism*; D066298:In Vitro Techniques; D007211:Indoles / Q000378:metabolism*; D007650:Ketanserin / Q000493:pharmacokinetics; D008745:Methylation; D011869:Radioligand Assay; D051381:Rats; D011919:Rats, Inbred Strains; D011985:Receptors, Serotonin / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship
D000588:Amines; D006213:Hallucinogens; D007211:Indoles; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D004290:DOM 2,5-Dimethoxy-4-Methylamphetamine; C003943:2,5-dimethoxy-4-bromoamphetamine; D012701:Serotonin; D007650:Ketanserin