Selective 5-hydroxytryptamine 2C receptor agonists derived from the lead compound tranylcypromine: identification of drugs with antidepressant-like action.
We report here the design, synthesis, and pharmacological properties of a series of compounds related to tranylcypromine (9), which itself was discovered as a lead compound in a high-throughput screening campaign. Starting from 9, which shows modest activity as a 5-HT(2C) agonist, a series of 1-aminomethyl-2-phenylcyclopropanes was investigated as 5-HT(2C) agonists through iterative structural modifications. Key pharmacophore feature of this new class of ligands is a 2-aminomethyl-trans-cyclopropyl side chain attached to a substituted benzene ring. Among the tested compounds, several were potent and efficacious 5-HT(2C) receptor agonists with selectivity over both 5-HT(2A) and 5-HT(2B) receptors in functional assays. The most promising compound is 37, with 120- and 14-fold selectivity over 5-HT(2A) and 5-HT(2B), respectively (EC(50) = 585, 65, and 4.8 nM at the 2A, 2B, and 2C subtypes, respectively). In animal studies, compound 37 (10-60 mg/kg) decreased immobility time in the mouse forced swim test.
Cho
Sung Jin
SJ
Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois 60612-7230, USA.
Jensen
Niels H
NH
Kurome
Toru
T
Kadari
Sudhakar
S
Manzano
Michael L
ML
Malberg
Jessica E
JE
Caldarone
Barbara
B
Roth
Bryan L
BL
Kozikowski
Alan P
AP
D000818:Animals; D000928:Antidepressive Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D003521:Cyclopropanes / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D008297:Male; D008744:Methylamines / Q000138:chemical synthesis* / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D011869:Radioligand Assay; D058826:Serotonin 5-HT2 Receptor Agonists; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014191:Tranylcypromine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology
C540180:(2-(3-methylphenyl)cyclopropyl)methylamine; D000928:Antidepressive Agents; D003521:Cyclopropanes; D008744:Methylamines; D008996:Monoamine Oxidase Inhibitors; D058826:Serotonin 5-HT2 Receptor Agonists; D014191:Tranylcypromine; D002118:Calcium