title: SKF83959 is a potent allosteric modulator of sigma-1 receptor.
abstract: SKF83959 (3-methyl-6-chloro-7,8-hydroxy-1-[3-methylphenyl]-2,3,4,5-tetrahydro-1H-3-benzazepine), an atypical dopamine receptor-1 (D(1) receptor) agonist, has shown many D(1) receptor-independent effects, such as neuroprotection, blockade of Na(+) channel, and promotion of spontaneous glutamate release, which resemble the effects of the sigma-1 receptor activation. In the present work, we explored the potential modulation of SKF83959 on the sigma-1 receptor. The results indicated that SKF83959 dramatically promoted the binding of (3)H(+)-pentazocine (a selective sigma-1 receptor agonist) to the sigma-1 receptor in brain and liver tissues but produced no effect on (3)H-progesterone binding (a sigma-1 receptor antagonist). The saturation assay and the dissociation kinetics assay confirmed the allosteric effect. We further demonstrated that the SKF83959 analogs, such as SCH22390 [(R)-(1)-7-chloro-8- hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride] and SKF38393 [(+/-)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrobromide], also showed the similar allosteric effect on the sigma-1 receptor in the liver tissue but not in the brain tissue. Moreover, all three tested chemicals elicited no significant effect on (3)H-1,3-di(2-tolyl)-guanidine ((3)H-DTG) binding to the sigma-2 receptor. The present data uncovered a new role of SKF83959 and its analogs on the sigma-1 receptor, which, in turn, may reveal the underlying mechanism for the D(1) receptor-independent effect of the drug.
authors.affiliation: Department of Pharmacology II, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Guo
authors.forename: Jianghao
authors.initials: J
authors.lastname: Zhao
authors.forename: Guozhang
authors.initials: G
authors.lastname: Jin
authors.forename: Bin
authors.initials: B
authors.lastname: Zhao
authors.forename: Guanghui
authors.initials: G
authors.lastname: Wang
authors.forename: Ao
authors.initials: A
authors.lastname: Zhang
authors.forename: Xuechu
authors.initials: X
authors.lastname: Zhen
mesh_terms: D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D004357:Drug Synergism; D057809:HEK293 Cells; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D010423:Pentazocine / Q000494:pharmacology*; D011374:Progesterone / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000819:agonists / Q000378:metabolism; D017480:Receptors, sigma / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000097605:Sigma-1 Receptor
chemical_list: D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D010423:Pentazocine; D011374:Progesterone; D017447:Receptors, Dopamine D1; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C106107:sigma-2 receptor; C080703:SK&F 83959