Discovery of N-Aryl Piperazines as Selective mGluR5 Potentiators with Improved In Vivo Utility

被引：35

作者：

Zhou, Ya ^{[1
,3
]}

Manka, Jason T. ^{[1
,3
]}

Rodriguez, Alice L. ^{[1
,3
]}

Weaver, C. David ^{[1
,3
,5
]}

Days, Emily L. ^{[3
,5
]}

Vinson, Paige N. ^{[1
,3
]}

Jadhav, Satyawan ^{[1
,3
]}

Hermann, Elizabeth J. ^{[1
,3
]}

Jones, Carrie K. ^{[1
,3
,4
]}

Conn, P. Jeffrey ^{[1
,3
]}

Lindsley, Craig W. ^{[1
,2
,3
]}

Stauffer, Shaun R. ^{[1
,3
]}

机构：

[1] Vanderbilt Univ, Med Ctr, Dept Pharmacol, Nashville, TN 37232 USA

[2] Vanderbilt Univ, Med Ctr, Dept Chem, Nashville, TN 37232 USA

[3] Vanderbilt Univ, Med Ctr, Vanderbilt Program Drug Discovery, Nashville, TN 37232 USA

[4] Tennessee Valley Healthcare Syst, US Dept Vet Affairs, Nashville, TN 37212 USA

[5] Vanderbilt Inst Chem Biol, Nashville, TN 37232 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2010年 / 1卷 / 08期

关键词：

mGluR; potentiator; positive allosteric modulator; schizophrenia; hyperlocomotion; POSITIVE ALLOSTERIC MODULATORS; GLUTAMATE-RECEPTOR SUBTYPE-5; ANTIPSYCHOTIC-LIKE; SERIES; SAR;

D O I：

10.1021/ml100181a

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

This letter describes the discovery, structure-activity relationship, and in vitro and in vivo pharmacological profile of a novel non-MPEP-derived mGluR(5) positive allosteric modulator (PAM) based upon an N-aryl piperazine chemotype. This mGluR(5) chemotyper exhibits the ability to act as either a noncompetitive antagonist/negative allosteric modulator or a potentiator of the glutamate response, depending on the identity of the amide substituent, that is, a molecular switch". A rapidly optimized PAM, 10e (VU0364289), was shown to be potent and specific for the rat mGluR(5) receptor and subsequently demonstrated to be efficacious in a clinically relevant rodent model predictive of antipsychotic activity, thus providing the first example of a centrally active mGluR(5) PAM optimized from an HTS-derived mGluR(5) noncompetitive antagonist.

引用

页码：433 / 438

页数：6

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