(+)-SK&F 10047 hydrochloride

IC50: N/A

SKF 10047 hydrochloride is a prototypical σ1 receptor agonist. Behaviorally active in animal models of memory and stress. It has been fully demonstrated that σ binding sites are distinct from phencyclidine binding sites on the NMDA receptor-ion channel complex, which has investigated extensively the functional role of σ receptors in the central nervous system [1,2].

In vitro: The effects of the stereoisomers of N-allylnormetazocine (SKF-10,047) were compared in rats on the hippocampal cholinergic functions. A putative σ1 receptor agonist, (+)-SKF-10,047, increased hippocampal extracellular acetylcholine level as well as anti-amnesic effect against scopolamine-induced memory dysfunctions in rats. Haloperidol, a putative σ1 receptor antagonist reversed these phenomena which were not produced by (-)-SKF-10,047. Such stereoselectivity and antagonism imply σ1 receptors involved in these (+)-SKF-10,047-stimulated hippocampal cholinergic functions [2].

In vivo: (+)-SKF-10,047 and dextromethorphan, being co-administered with phenytoin (10 mg/kg, an anticonvulsant drug), decreased conditioned fear stress with low doses (4 and 20 mg/kg, respectively). The effects were antagonized by the σ receptor antagonists, NE-100 and BMY-14802. Furthermore, the effects of (+)-SKF-10,047 or dextromethorphan plus phenytoin were inhibited by the dopamine D1 receptor antagonist (SCH 23390) and the dopamine D2 receptor antagonist ((-)-sulpiride), and they were also decreased by 6-hydroxydopamine-induced lesions of dopaminergic neurons. The ameliorating effects of (+)-SKF-10,047 and dextromethorphan on condition of fear stress using high doses (5 and 30 mg/kg, respectively) were also inhibited by both the dopamine receptor antagonists [3].

Clinical trial: So far, no clinical study has been conducted.

References:
[1] Walker JM, Bowen WD, Walker FO, Matsumoto RR, De Costa B, Rice KC.  Sigma receptors: biology and function. Pharmacol Rev. 1990 Dec;42(4):355-402.
[2] Matsuno K, Senda T, Kobayashi T, Mita S.  Involvement of sigma 1 receptor in (+)-N-allylnormetazocine-stimulated hippocampal cholinergic functions in rats. Brain Res. 1995 Sep 4; 690 (2): 200-6.
[3].  Kamei H, Kameyama T, Nabeshima T. (+)-SKF-10,047 and dextromethorphan ameliorate conditioned fear stress via dopaminergic systems linked to phenytoin-regulated sigma 1 sites. Eur J Pharmacol. 1996 Aug 8;309(2):149-58.

(+)-SKF-10,047 and dextromethorphan ameliorate conditioned fear stress via dopaminergic systems linked to phenytoin-regulated sigma 1 sites.[Pubmed:8874133]

Eur J Pharmacol. 1996 Aug 8;309(2):149-58.

Mice exhibited a marked suppression of motility when they were re-placed in the same environment in which they had previously received an electric footshock. (+)-SKF-10,047 ([2S-(2 alpha, 6 alpha, 11R*)]-1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(2-propenyl)-2,6-me tha no-3-benzazocin-8-ol hydrochloride; (+)-N-allylnormetazocine hydrochloride) and dextromethorphan, putative sigma receptor agonists, have been reported to reserve this psychological stress-induced motor suppression, defined as conditioned fear stress, through phenytoin-regulated type sigma 1, receptors. In the present study, we investigated the involvement of dopaminergic neurons in the ameliorating effects of (+)-SKF-10,047 and dextromethorphan on conditioned fear stress. (+)-SKF-10,047 and dextromethorphan attenuated conditioned fear stress at low doses (4 and 20 mg/kg, respectively) when they were co-administered with phenytoin (10 mg/kg), an anticonvulsant drug. The effects were antagonized by the sigma receptor antagonists. NE-100 (N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]-ethylamine monohydrochloride) and BMY-14802 (a-(4-fluoro-phenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine-butanol hydrochloride). Furthermore, the effects of (+)-SKF-10,047 or dextromethorphan in combination with phenytoin were blocked by the dopamine D1 receptor antagonist. SCH 23390 (R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3- benzazepine), and the dopamine D2 receptor antagonist, (-)-sulpiride, and they were also attenuated by 6-hydroxydopamine-induced lesions of dopaminergic neurons. The ameliorating effects of (+)-SKF-10,047 and dextromethorphan on conditioned fear stress at high doses (5 and 30 mg/kg, respectively) were also blocked by both the dopamine receptor antagonists. These results suggest that the stress-induced motor suppression is restored by the activation of dopaminergic neuronal systems as a result of the stimulation of phenytoin-regulated type sigma 1 receptors.

Involvement of sigma 1 receptor in (+)-N-allylnormetazocine-stimulated hippocampal cholinergic functions in rats.[Pubmed:8535837]

Brain Res. 1995 Sep 4;690(2):200-6.

The effects of the stereoisomers of N-allylnormetazocine (SKF-10,047) on the hippocampal cholinergic functions were compared in rats. A putative sigma 1 receptor agonist, (+)-SKF-10,047, elicited an increase of hippocampal extracellular acetylcholine level and anti-amnesic effect against scopolamine-induced memory dysfunctions in rats. These phenomena were not produced by (-)-SKF-10,047, and were reversed by haloperidol, a putative sigma 1 receptor antagonist. Such stereoselectivity and antagonism imply an involvement of sigma 1 receptors in these (+)-SKF-10,047-stimulated hippocampal cholinergic functions.