title: Synthesis and in vitro biological evaluation of carbonyl group-containing inhibitors of vesicular acetylcholine transporter.
abstract: To identify selective high-affinity inhibitors of the vesicular acetylcholine transporter (VAChT), we have interposed a carbonyl group between the phenyl and piperidyl groups of the prototypical VAChT ligand vesamicol and its more potent analogues benzovesamicol and 5-aminobenzovesamicol. Of 33 compounds synthesized and tested, 6 display very high affinity for VAChT (K(i), 0.25-0.66 nM) and greater than 500-fold selectivity for VAChT over sigma(1) and sigma(2) receptors. Twelve compounds have high affinity (K(i), 1.0-10 nM) and good selectivity for VAChT. Furthermore, 3 halogenated compounds, namely, trans-3-[4-(4-fluorobenzoyl)piperidinyl]-2-hydroxy-1,2,3,4-tetrahydronaphthalene (28b) (K(i) = 2.7 nM, VAChT/sigma selectivity index = 70), trans-3-[4-(5-iodothienylcarbonyl)piperidinyl]-2-hydroxy-1,2,3,4-tetrahydronaphthalene (28h) (K(i) = 0.66 nM, VAChT/sigma selectivity index = 294), and 5-amino-3-[4-(p-fluorobenzoyl)piperidinyl]-2-hydroxy-1,2,3,4,-tetrahydronaphthalene (30b) (K(i) = 2.40 nM, VAChT/sigma selectivity index = 410) display moderate to high selectivity for VAChT. These three compounds can be synthesized with the corresponding radioisotopes so as to serve as PET/SPECT probes for imaging the VAChT in vivo.
authors.affiliation: Departments of Radiology, Medicinal Chemistry and Neurosurgery, University of Minnesota, Minneapolis, Minnesota 55455, USA.
authors.forename: Simon M N
authors.initials: SM
authors.lastname: Efange
authors.forename: Anil B
authors.initials: AB
authors.lastname: Khare
authors.forename: Krystyna
authors.initials: K
authors.lastname: von Hohenberg
authors.forename: Robert H
authors.initials: RH
authors.lastname: Mach
authors.forename: Stanley M
authors.initials: SM
authors.lastname: Parsons
authors.forename: Zhude
authors.initials: Z
authors.lastname: Tu
mesh_terms: D000818:Animals; D055808:Drug Discovery; D006168:Guinea Pigs; D020128:Inhibitory Concentration 50; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D014101:Torpedo; D050494:Vesicular Acetylcholine Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D010880:Piperidines; D050494:Vesicular Acetylcholine Transport Proteins; C006189:vesamicol