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Selective 5-hydroxytryptamine 2C Receptor Agonists Derived From the Lead Compound Tranylcypromine: Identification of Drugs With Antidepressant-Like Action

Selective 5-hydroxytryptamine 2C Receptor Agonists Derived From the Lead Compound Tranylcypromine: Identification of Drugs With Antidepressant-Like Action

Sung Jin Cho, Niels H Jensen, Toru Kurome, Sudhakar Kadari, Michael L Manzano, Jessica E Malberg, Barbara Caldarone, Bryan L Roth, Alan P Kozikowski

J Med Chem. 2009 Apr 9;52(7):1885-902.

PMID: 19284718

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP54779587	Tranylcypromine Related Compound A		54779-58-7	Price

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