Dual probes for the dopamine transporter and sigma1 receptors: novel piperazinyl alkyl-bis(4'-fluorophenyl)amine analogues as potential cocaine-abuse therapeutic agents.
Both dopamine uptake inhibitors and sigma(1) receptor antagonists have been implicated as potential pharmacotherapeutics for the treatment of cocaine abuse. While the dopamine uptake inhibitors may share with cocaine neurochemical mechanisms underlying reinforcing properties, sigma(1) antagonists have been shown to attenuate some behavioral actions and toxic side effects associated with cocaine overdose. Rimcazole, a sigma(1) receptor antagonist that binds to the DAT (K(i) = 224 nM), is not behaviorally cocaine-like and attenuates some of the behavioral actions of cocaine. To determine the roles of both DAT and sigma(1) receptors in the behavioral actions of rimcazole, a series of analogues was synthesized. Initial studies identified two analogues (1 and 4) that showed high to moderate affinities for both DAT and sigma(1) receptors and failed to show cocaine-like discriminative stimulus (DS) effects. A second series of bis(4'-fluorophenyl)amine analogues have now been prepared in which the most potent DAT compound, 19 (K(i) = 8.5 nM), was selective over serotonin transporter (SERT/DAT = 94), norepinephrine transporter (NET/DAT = 63), and sigma(1) receptor binding (sigma(1)/DAT = 44). In addition, two other analogues 10 and 17 showed superior selectivity for DAT over SERT (170- and 140-fold, respectively) and DAT over NET (219- and 190-fold, respectively) but were essentially equipotent at DAT and sigma(1) receptors (10; K(i) = 77 and 124 nM, respectively, 17; K(i) = 28 and 13 nM, respectively). CoMFA studies at both DAT and sigma(1) receptors were performed to examine structural requirements for optimal binding at these two targets as well as to assess differences between them. Behavioral evaluation of analogues with varying affinities for both DAT and sigma(1) receptors may provide a novel approach toward designing medications for cocaine abuse.
Cao
Jianjing
J
Medicinal Chemistry, NIDA-IRP, Baltimore, Maryland 21224, USA.
Kulkarni
Santosh S
SS
Husbands
Stephen M
SM
Bowen
Wayne D
WD
Williams
Wanda
W
Kopajtic
Theresa
T
Katz
Jonathan L
JL
George
Clifford
C
Newman
Amy Hauck
AH
D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D019970:Cocaine-Related Disorders / Q000188:drug therapy*; D018360:Crystallography, X-Ray; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins; D066298:In Vitro Techniques; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins / Q000378:metabolism*; D008958:Models, Molecular; D009419:Nerve Tissue Proteins; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017480:Receptors, sigma / Q000187:drug effects*; D013329:Structure-Activity Relationship
D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D010879:Piperazines; D017480:Receptors, sigma; C493216:Slc6a3 protein, rat; D004298:Dopamine