1. Pyrrolidine analogs of GZ-793A: synthesis and evaluation as inhibitors of the vesicular monoamine transporter-2 (VMAT2).
- Author
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Penthala NR, Ponugoti PR, Nickell JR, Deaciuc AG, Dwoskin LP, and Crooks PA
- Subjects
- Animals, Binding Sites, Dopamine metabolism, Lobeline chemical synthesis, Lobeline chemistry, Lobeline metabolism, Protein Binding, Pyrrolidines chemical synthesis, Pyrrolidines metabolism, Rats, Synaptic Vesicles metabolism, Tetrabenazine analogs & derivatives, Tetrabenazine chemistry, Tetrabenazine metabolism, Vesicular Monoamine Transport Proteins metabolism, Lobeline analogs & derivatives, Pyrrolidines chemistry, Vesicular Monoamine Transport Proteins antagonists & inhibitors
- 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 [(3)H]-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 [(3)H]-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., (Copyright © 2013. Published by Elsevier Ltd.)
- Published
- 2013
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