Pyrrolidine analogs of GZ-793A: Synthesis and evaluation as inhibitors of the vesicular monoamine transporter-2 (VMAT2)

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:23

Article

Penthala, Narsimha Reddy¹  Ponugoti, Purushothama Rao²  Nickell, Justin R.²  Deaciuc, Agripina G.²  Dwoskin, Linda P.²  Crooks, Peter A.¹ 

[1] Univ Arkansas Med Sci, Coll Pharm, Dept Pharmaceut Sci, Little Rock, AR 72205 USA

[2] Univ Kentucky, Coll Pharm, Dept Pharmaceut Sci, Lexington, KY 40536 USA

关键词: Pyrrolidine analogs;    GZ-793A;    Dihydrotetrabenazine binding site;    Vesicular monoamine transporter-2;    N-Propane-1,2(R)-diols;   

DOI  :  10.1016/j.bmcl.2013.03.092

来源: Elsevier

【 摘 要 】

Central heterocyclic ring size reduction from piperidinyl to pyrrolidinyl in the vesicular monoamine transporter-2 (VMAT2) inhibitor GZ-793A and its analogs resulted in novel N-propane-1,2(R)-diol analogs 11a-i. These compounds were evaluated for their affinity for the dihydrotetrabenazine (DTBZ) binding site on VMAT2 and for their ability to inhibit vesicular dopamine (DA) uptake. The 4-difluoromethoxy-phenethyl analog 11f was the most potent inhibitor of [H-3]-DTBZ binding (K-i = 560 nM), with 15-fold greater affinity for this site than GZ-793A (K-i = 8.29 mu M). Analog 11f also showed similar potency of inhibition of [3H]-DA uptake into vesicles (K-i = 45 nM) compared to that for GZ-793A (K-i = 29 nM). Thus, 11f represents a new water-soluble inhibitor of VMAT function. (C) 2013 Elsevier Ltd. All rights reserved.

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