| Title | Selective 5-Hydroxytryptamine 2C Receptor Agonists Derived from the Lead Compound Tranylcypromine: Identification of Drugs with Antidepressant-Like Action. | | Author(s) | Cho SJ, Jensen NH, Kurome T, Kadari S, Manzano ML, Malberg JE, Caldarone B, Roth BL, Kozikowski AP | | Institution | Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy (M/C781), University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612-7230, Department of Pharmacology, Psychiatry, Comprehensive Cancer Center, Center for Neurobiology Division of Medicinal Chemistry and Natural Products, and NIMH Psychoactive Drug Screening Program, University of North Carolina Medical School, Chapel Hill, CB 7365, North Carolina 27599, Psychogenics, Inc., Tarrytown, New York 10591. | | Source | J Med Chem 2009 Mar 13. | | Abstract | 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. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 19284718 |
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