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

Narsimha Reddy Penthala, Purushothama Rao Ponugoti, Justin R. Nickell, Agripina G. Deaciuc, Linda P. Dwoskin, Peter A. Crooks

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

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-difluoromethoxyphenethyl analog 11f was the most potent inhibitor of [3H]-DTBZ binding (Ki = 560 nM), with 15-fold greater affinity for this site than GZ-793A (Ki = 8.29 μM). Analog 11f also showed similar potency of inhibition of [3H]-DA uptake into vesicles (Ki = 45 nM) compared to that for GZ-793A (Ki = 29 nM). Thus, 11f represents a new water-soluble inhibitor of VMAT function.

Original languageEnglish
Pages (from-to)3342-3345
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume23
Issue number11
DOIs
StatePublished - Jun 1 2013

Bibliographical note

Funding Information:
This research was supported by NIH grant U01 DA13519 . The University of Kentucky holds patents on lobeline and the analogues described in the current work. A potential royalty stream to L.P.D. and P.A.C. may occur consistent with University of Kentucky policy.

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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