title: Assessment of mazindane, a pro-drug form of mazindol, in assays used to define cocaine treatment agents.
abstract: The current studies compared mazindane (5-(4-chlorophenyl)-2,3-dihydro-5H-imidazo [2,1a] isoindole) hydrogen sulfate, a water soluble pro-drug of mazindol (5-(4-chlorophenyl-2,3-dihydro-5H-imidazo [2,1-a] isoindol-5-ol), with mazindol in assays used to define cocaine treatment agents. Both compounds enhanced motor activity (LMA) in Swiss Webster mice with ED(50) values of 2.5 mg/kg i.p. for mazindane and 3.9 mg/kg i.p. for mazindol. At 25 mg/kg mazindane displayed toxic effects and death while mazindol was effect/death free at 50 mg/kg. In Sprague-Dawley rats trained to discriminate cocaine from saline both compounds fully substituted for cocaine with mazindane being fourfold more potent in the total session (0.33 vs. 1.3 mg/kg i.p.) and first reinforcer (0.29 vs. 1.2 mg/kg i.p). Complete substitution was observed in rhesus monkeys trained to discriminate cocaine from saline with ED(50) values for mazindane (0.134 mg/kg i.m.) and mazindol (0.119 mg/kg i.m.). Mazindol exhibited little or no activity at 10(-5) M in inhibiting radioligand binding at 14 neurotransmitter sites while mazindane gave weak activity at the histamine H(1) and 5-hydroxytryptamine 5-HT(3) sites. These results demonstrate that mazindane could be a useful alternative to mazindol as a pharmacological tool because of its similar profile of activity and enhanced water solubility.
authors.affiliation: C.A. Dana Research Institute, Drew University, Madison, NJ 07940, USA. whouliha@drew.edu
authors.forename: William J
authors.initials: WJ
authors.lastname: Houlihan
authors.forename: Lawrence
authors.initials: L
authors.lastname: Kelly
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002462:Cell Membrane / Q000378:metabolism; D003042:Cocaine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D004193:Discrimination Learning / Q000187:drug effects; D004192:Discrimination, Psychological / Q000187:drug effects*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D054833:Isoindoles; D008253:Macaca mulatta; D008297:Male; D008454:Mazindol / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D018377:Neurotransmitter Agents / Q000378:metabolism; D011335:Proadifen / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014316:Tritium
chemical_list: D018765:Dopamine Uptake Inhibitors; D054833:Isoindoles; D018377:Neurotransmitter Agents; C465766:mazindane; D014316:Tritium; C021279:(1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester; D011335:Proadifen; D008454:Mazindol; D003042:Cocaine