Rational drug design leading to the identification of a potent 5-HT 2C agonist lacking 5-HT 2B activity

Gang Chen; Sung Jin Cho; Xi Ping Huang; Niels H. Jensen; Andreas Svennebring; Maria F. Sassano; Bryan L. Roth; Alan P. Kozikowski

doi:10.1021/ml200206z

Rational drug design leading to the identification of a potent 5-HT _2C agonist lacking 5-HT _2B activity

Gang Chen, Sung Jin Cho, Xi Ping Huang, Niels H. Jensen, Andreas Svennebring, Maria F. Sassano, Bryan L. Roth, Alan P. Kozikowski

Research output: Contribution to journal › Article › peer-review

14 Scopus citations

Abstract

The 5-HT _2C receptor is an attractive drug target in the quest for new therapeutics to treat a variety of human disorders. We have previously undertaken a structural optimization campaign that has led to some potent and moderately selective 5-HT _2C receptor agonists. After expanding our structure-function library, we were able to combine our data sets so as to allow the design of compounds of improved selectivity and potency. We disclose herein the structural optimization of our previously reported 5-HT _2B/5- HT _2C agonists, which has led to the identification of a highly selective 5-HT _2C agonist, (+)-trans-[2-(2-cyclopropylmethoxyphenyl) cyclopropyl]methylamine hydrochloride, with an EC ₅₀ of 55 nM and no detectable agonism at the 5-HT _2B receptor.

Original language	English (US)
Pages (from-to)	929-932
Number of pages	4
Journal	ACS Medicinal Chemistry Letters
Volume	2
Issue number	12
DOIs	https://doi.org/10.1021/ml200206z
State	Published - Dec 8 2011
Externally published	Yes

Keywords

5-HT receptor
5-HT receptor
Serotonin
agonist
hydrophobic interactions

ASJC Scopus subject areas

Biochemistry
Drug Discovery
Organic Chemistry

Access to Document

10.1021/ml200206z

Cite this

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title = "Rational drug design leading to the identification of a potent 5-HT 2C agonist lacking 5-HT 2B activity",

abstract = "The 5-HT 2C receptor is an attractive drug target in the quest for new therapeutics to treat a variety of human disorders. We have previously undertaken a structural optimization campaign that has led to some potent and moderately selective 5-HT 2C receptor agonists. After expanding our structure-function library, we were able to combine our data sets so as to allow the design of compounds of improved selectivity and potency. We disclose herein the structural optimization of our previously reported 5-HT 2B/5- HT 2C agonists, which has led to the identification of a highly selective 5-HT 2C agonist, (+)-trans-[2-(2-cyclopropylmethoxyphenyl) cyclopropyl]methylamine hydrochloride, with an EC 50 of 55 nM and no detectable agonism at the 5-HT 2B receptor.",

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AU - Jensen, Niels H.

AU - Svennebring, Andreas

AU - Sassano, Maria F.

AU - Roth, Bryan L.

AU - Kozikowski, Alan P.

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