title: Pyrrolidine analogs of GZ-793A: synthesis and evaluation as inhibitors of the vesicular monoamine transporter-2 (VMAT2).
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.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors.forename: Narsimha Reddy
authors.initials: NR
authors.lastname: Penthala
authors.forename: Purushothama Rao
authors.initials: PR
authors.lastname: Ponugoti
authors.forename: Justin R
authors.initials: JR
authors.lastname: Nickell
authors.forename: Agripina G
authors.initials: AG
authors.lastname: Deaciuc
authors.forename: Linda P
authors.initials: LP
authors.lastname: Dwoskin
authors.forename: Peter A
authors.initials: PA
authors.lastname: Crooks
mesh_terms: D000818:Animals; D001665:Binding Sites; D004298:Dopamine / Q000378:metabolism; D008120:Lobeline / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D051381:Rats; D013572:Synaptic Vesicles / Q000378:metabolism; D013747:Tetrabenazine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D050493:Vesicular Monoamine Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C573789:N-(1,2-dihydroxylpropyl)-2,6-di-(4-methoxyphenethyl)piperidine; D011759:Pyrrolidines; D050493:Vesicular Monoamine Transport Proteins; C032811:dihydrotetrabenazine; D008120:Lobeline; C032519:pyrrolidine; D004298:Dopamine; D013747:Tetrabenazine