title: Structure-activity comparison of YZ-069, a novel sigma ligand, and four analogs in receptor binding and behavioral studies.
abstract: Earlier studies show that antagonism of sigma receptors using high to moderate affinity compounds or antisense oligodeoxynucleotides targeting the sigma(1) subtype significantly attenuates the behavioral effects of cocaine in mice. In this study, the novel sigma receptor ligand YZ-069 [N-phenylpropyl-N'-(3,4-dichlorophenethyl)piperazine] and four analogs (representing nitrophenyl and methoxyphenyl derivatives) were evaluated in receptor binding and behavioral studies to further delineate structural features that convey favorable anticocaine actions. In receptor binding studies, all of the compounds had low nanomolar affinities for sigma(1) and sigma(2) receptors but only micromolar affinities for monoamine transporters. Consistent with the favorable affinities of the compounds for sigma receptors, they also significantly attenuated cocaine-induced convulsions in mice. The compounds with the 3,4-dichlorophenyl and methoxyphenyl substitutions provided better protection against cocaine-induced convulsions than the nitrophenyl derivative. This is consistent with the reduced lipophilicity of the nitro substitution, which would reduce its ability to cross the blood-brain barrier. The position of the substituent on the phenyl ring had no significant effect on binding affinity or behavioral protective actions. Together with earlier studies, the data suggest that favorable features of sigma receptor ligands with anticocaine actions include high affinity for brain sigma receptors, antagonistic actions at the receptor, and lipophilicity to facilitate crossing the blood-brain barrier.
authors.affiliation: Department of Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, PO Box 26901, Oklahoma City, OK 73190, USA. rae-matsumoto@ouhsc.edu
authors.forename: Rae R
authors.initials: RR
authors.lastname: Matsumoto
authors.forename: Florence Hourcade
authors.initials: FH
authors.lastname: Potelleret
authors.forename: Aisha
authors.initials: A
authors.lastname: Mack
authors.forename: Buddy
authors.initials: B
authors.lastname: Pouw
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Wayne D
authors.initials: WD
authors.lastname: Bowen
mesh_terms: D000818:Animals; D003042:Cocaine / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D008024:Ligands; D008297:Male; D051379:Mice; D010879:Piperazines / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017480:Receptors, sigma / Q000378:metabolism*; D012640:Seizures / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D010879:Piperazines; D017480:Receptors, sigma; D003042:Cocaine