Discovery of a novel potent GABA(B) receptor agonist

Feng Xu; Ge Peng; Thu Phan; Usha Dilip; Jian Lu Chen; Tania Chernov-Rogan; Xuexiang Zhang; Kent Grindstaff; Thamil Annamalai; Kerry Koller; Mark A Gallop; David J Wustrow

doi:10.1016/j.bmcl.2011.08.006

Discovery of a novel potent GABA(B) receptor agonist

Bioorg Med Chem Lett. 2011 Nov 1;21(21):6582-5. doi: 10.1016/j.bmcl.2011.08.006. Epub 2011 Aug 17.

Authors

Feng Xu¹, Ge Peng, Thu Phan, Usha Dilip, Jian Lu Chen, Tania Chernov-Rogan, Xuexiang Zhang, Kent Grindstaff, Thamil Annamalai, Kerry Koller, Mark A Gallop, David J Wustrow

Affiliation

¹ XenoPort Inc., 3410 Central Expressway, Santa Clara, CA 95051, USA.

PMID: 21920749
DOI: 10.1016/j.bmcl.2011.08.006

Abstract

Structure-activity studies have led to a discovery of 3-(4-pyridyl)methyl ether derivative 9d that has 25- to 50-fold greater functional potency than R-baclofen at human and rodent GABA(B) receptors in vitro. Mouse hypothermia studies confirm that this compound crosses the blood-brain barrier and is approximately 50-fold more potent after systemic administration.

MeSH terms

Animals
Baclofen / chemistry
Baclofen / pharmacokinetics
Baclofen / pharmacology*
Blood-Brain Barrier
Drug Discovery*
GABA Agonists / chemistry
GABA Agonists / pharmacokinetics
GABA Agonists / pharmacology*
Humans
Mice
Receptors, GABA-B / drug effects*

Substances

GABA Agonists
Receptors, GABA-B
Baclofen