Pyrrolidine analogs of GZ-793A: Synthesis and evaluation as inhibitors of the vesicular monoamine transporter-2 (VMAT2) |
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Authors: | Narsimha Reddy Penthala Purushothama Rao Ponugoti Justin R Nickell Agripina G Deaciuc Linda P Dwoskin Peter A Crooks |
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Institution: | 1. Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA;2. Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA |
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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. |
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Keywords: | Pyrrolidine analogs GZ-793A Dihydrotetrabenazine binding site Vesicular monoamine transporter-2 |
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