RESUMO
Variation of the methoxycarbonyl and C-18 substituents of the antiaddictive compound 18-methoxycoronaridine, and contraction of its isoquinuclidine ring segment, provided 15 congeners for SAR evaluation at opioid and alpha3beta4 nicotinic acetylcholine receptors. The opioid activities were relatively low, and the alpha3beta4 nicotinic acetylcholine receptor activities were found to correlate with in vivo antiaddictive activities.
Assuntos
Ibogaína/análogos & derivados , Ibogaína/síntese química , Receptores Nicotínicos/efeitos dos fármacos , Receptores Opioides/efeitos dos fármacos , Transtornos Relacionados ao Uso de Substâncias/tratamento farmacológico , Animais , Linhagem Celular , Humanos , Ibogaína/química , Ibogaína/farmacologia , Dependência de Morfina/tratamento farmacológico , Técnicas de Patch-Clamp , Ratos , Receptores Nicotínicos/fisiologia , Receptores Opioides/fisiologia , Autoadministração , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
18-Methoxycoronaridine, a novel iboga alkaloid congener, reduces drug self-administration in animal models of addiction. Previously, we proposed that these effects are mediated by the ability of 18-methoxycoronaridine to inhibit nicotinic alpha3beta4 acetylcholine receptors. In an attempt to identify more potent 18-methoxycoronaridine analogs, we have tested a series of 18-methoxycoronaridine congeners by whole-cell patch clamp recording of HEK 293 cells expressing recombinant nicotinic alpha3beta4 receptors or glutamate NR1/NR2B N-methyl-d-aspartate (NMDA) receptors. The congeners exhibited a range of inhibitory potencies at alpha3beta4 receptors. Five congeners had IC(50) values similar to 18-methoxycoronaridine, and all of these were ineffective at NMDA receptors. The congeners also retained their ability to reduce morphine and methamphetamine self-administration. These data are consistent with the importance of nicotinic alpha3beta4 receptors as a therapeutic target to modulate drug seeking. These compounds may constitute a new class of synthetic agents that act via the nicotinic alpha3beta4 mechanism to combat addiction.
Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/tratamento farmacológico , Ibogaína/análogos & derivados , Ibogaína/farmacologia , Dependência de Morfina/tratamento farmacológico , Antagonistas Nicotínicos/farmacologia , Receptores Nicotínicos/efeitos dos fármacos , Tabernaemontana , Animais , Linhagem Celular , Relação Dose-Resposta a Droga , Feminino , Humanos , Ibogaína/administração & dosagem , Antagonistas Nicotínicos/administração & dosagem , Técnicas de Patch-Clamp , Ratos , Ratos Long-Evans , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores Nicotínicos/fisiologia , Recompensa , AutoadministraçãoRESUMO
New molecular platforms which are hybrids of two scaffolds-namely, beta-d-glucose and benzodiazepine, each able to bind several proteins-were designed, synthesized and functionalized to serve as probes for broad biological screening. Herein, we describe the syntheses and chemical properties of these novel chimeric scaffolds. Attempted cyclization of the functionalized analogues (-)-96 and (-)-97 afforded the corresponding dimers (-)-98 and (-)-99, respectively, under a variety of reaction conditions, even at concentrations of only 0.001 N. Consideration of factors affecting the conformation of amide bonds and their effects on cyclization reactions led us to alkylate the amide bond. As expected, the cyclization of the N-methyl derivative (-)-110 afforded exclusively the unimolecular cyclization product (+)-111. These compounds are only now undergoing broad screening and represent therefore at present a "prospecting library."