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.
|Number of pages||4|
|Journal||Bioorganic and Medicinal Chemistry Letters|
|State||Published - Jun 1 2013|
Bibliographical noteFunding 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.
- Dihydrotetrabenazine binding site
- Pyrrolidine analogs
- Vesicular monoamine transporter-2
ASJC Scopus subject areas
- Molecular Medicine
- Molecular Biology
- Pharmaceutical Science
- Drug Discovery
- Clinical Biochemistry
- Organic Chemistry