title: Synthesis and pharmacology of irreversible affinity labels as potential cocaine antagonists: aryl 1,4-dialkylpiperazines related to GBR-12783.
abstract: As part of a program aimed at designing irreversible antagonists of the stimulant and reinforcing properties of cocaine, derivatives of GBR-12783 containing electrophilic substituents were synthesized. GBR-12783, a potent and selective inhibitor of both stimulant binding and dopamine transport, was modified to incorporate either isothiocyanate or maleimido groups at the meta- or para-positions in one phenyl ring of the geminal diphenyl portion of the molecule. The effect of these compounds, as well as their respective amino- or nitro-substituted precursors, on stimulant binding to rat striatal tissue was studied using the [3H]methylphenidate radioreceptor assay. Under the assay conditions used, the compounds were found to have IC50s (nM) ranging from 11.9 (m-nitro) to 1677 (p-maleimido); the parent compound, GBR-12783, had an IC50 of 12.0. Using a washout technique (repeated washing with 100 mM KCl) which completely removed the tightly bound, but reversible GBR-12783, both the m- and p-isothiocyanate compounds were found to irreversibly inhibit binding of [3H]methylphenidate to the stimulant recognition site. The m-maleimido derivative also irreversibly inhibited binding, albeit with lower efficacy than was observed with the isothiocyanate compounds. Neither the p-maleimido, nor the amino or nitro intermediates, were capable of irreversible inhibition.
authors.affiliation: School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta 30332-0400.
authors.forename: H M
authors.initials: HM
authors.lastname: Deutsch
authors.forename: M M
authors.initials: MM
authors.lastname: Schweri
authors.forename: C T
authors.initials: CT
authors.lastname: Culbertson
authors.forename: L H
authors.initials: LH
authors.lastname: Zalkow
mesh_terms: D000818:Animals; D001665:Binding Sites; D003042:Cocaine / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D018492:Dopamine Antagonists; D066298:In Vitro Techniques; D017879:Isothiocyanates; D008297:Male; D008774:Methylphenidate / Q000378:metabolism*; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013861:Thiocyanates / Q000737:chemistry
chemical_list: D018492:Dopamine Antagonists; D017879:Isothiocyanates; D010879:Piperazines; D013861:Thiocyanates; D008774:Methylphenidate; C037152:isothiocyanic acid; C039737:1-(2-(diphenylmethoxy)ethyl)-4-(3-phenyl-2-propenyl)piperazine; D003042:Cocaine; D004298:Dopamine