N-methyl derivatives of the 5-HT2 agonist 1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropane.
1-(4-Bromo-2,5-dimethoxyphenyl)-2-aminopropane (DOB) is a serotonin (5-HT) agonist that displays a high affinity and selectivity for a certain population of central 5-HT binding sites (i.e., 5-HT2 sites). In the present study, (a) an enantiomeric potency comparison was made for the optical isomers of DOB and (b) the activity of N-monomethyl-,N,N-dimethyl-, and N,N,N-trimethyl-DOB was examined. (R)-(-)-DOB (Ki = 0.39 nM) was found to have 6 times greater affinity than its S-(+) enantiomer at [3H]DOB-labeled (rat cortical homogenates) 5-HT2 sites; N-methylation of racemic DOB resulted in a decrease in affinity that was at least 1 order of magnitude per methyl group. Similar results were obtained in an in vivo drug discrimination paradigm with rats as subjects and (R)-(-)-DOB (0.2 mg/kg) as the training drug. Thus, the R-(-) isomer of DOB is more active than its S-(+) enantiomer and than any of the possible N-methyl derivatives of DOB, both with respect to affinity at central 5-HT2 binding sites and with respect to potency in the behavioral (i.e., stimulus generalization) studies.
D000818:Animals; D001667:Binding, Competitive; D001969:Bromobenzenes / Q000378:metabolism / Q000494:pharmacology; D055598:Chemical Phenomena; D002621:Chemistry; D004193:Discrimination Learning / Q000187:drug effects; D005625:Frontal Lobe / Q000378:metabolism; D007536:Isomerism; D007650:Ketanserin / Q000378:metabolism; D008297:Male; D011437:Propylamines / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011985:Receptors, Serotonin / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D013329:Structure-Activity Relationship
D001969:Bromobenzenes; D011437:Propylamines; D011985:Receptors, Serotonin; D012701:Serotonin; D007650:Ketanserin