BD 1063 dihydrochloride

BD 1063 dihydrochloride is an antagonist of σ-1 receptor with Ki value of 9.15 nM [1].

σ-receptor is a type of opioid receptor. There are two subtypes of σ-receptor: σ-1 and σ-2.σ-1 receptor plays an important role in stimulating dopamine release and modulating the actions of cocaine [2].

BD 1063 dihydrochloride is a σ-1 receptor antagonist with Ki values of 9.15 and 449 nM for σ-1 receptor and σ-2 receptor, respectively. BD1063 reduced the dystonia induced by haloperidol and di-o-tolylguanidine (DTG) in a dose-dependent way [1].

In mice, BD1063 inhibited up-regulation of fra-2 and σ-1 receptor induced by cocaine in whole brain, cortex and striatum [2]. In mice, BD1063 significantly inhibited convulsions, lethality and locomotor stimulatory effects induced by cocaine [3]. In two excessive drinking rat models, BD-1063 reduced ethanol self-administration in a dose-dependent way and inhibited the expression of σ-1 receptor in the nucleus accumbens [4]. In mice, BD-1063 reversed thermal (radiant heat) hyperalgesia and inflammatory mechanical (paw pressure) in a dose-dependent way. However, BD-1063 had no effect on thermal hyperalgesia in σ1 knockout (σ1-KO) mice. These results suggested that σ1 receptor played an important role in inflammatory hyperalgesia [5].

References:
[1].  Matsumoto RR, Bowen WD, Tom MA, et al. Characterization of two novel sigma receptor ligands: antidystonic effects in rats suggest sigma receptor antagonism. Eur J Pharmacol, 1995, 280(3): 301-310.
[2].  Liu Y, Chen GD, Lerner MR, et al. Cocaine up-regulates Fra-2 and sigma-1 receptor gene and protein expression in brain regions involved in addiction and reward. J Pharmacol Exp Ther, 2005, 314(2): 770-779.
[3].  Matsumoto RR, McCracken KA, Friedman MJ, et al. Conformationally restricted analogs of BD1008 and an antisense oligodeoxynucleotide targeting sigma1 receptors produce anti-cocaine effects in mice. Eur J Pharmacol, 2001, 419(2-3): 163-174.
[4].  Sabino V, Cottone P, Zhao Y, et al. The sigma-receptor antagonist BD-1063 decreases ethanol intake and reinforcement in animal models of excessive drinking. Neuropsychopharmacology, 2009, 34(6): 1482-1493.
[5].  Tejada MA, Montilla-García A, Sánchez-Fernández C, et al. Sigma-1 receptor inhibition reverses acute inflammatory hyperalgesia in mice: role of peripheral sigma-1 receptors. Psychopharmacology (Berl), 2014, 231(19): 3855-3869.

Cocaine up-regulates Fra-2 and sigma-1 receptor gene and protein expression in brain regions involved in addiction and reward.[Pubmed:15879001]

J Pharmacol Exp Ther. 2005 Aug;314(2):770-9.

Sigma receptors have recently been implicated in the actions of cocaine, and antagonists of these receptors prevent many acute and subchronic cocaine effects. A previous study revealed that the immediate early gene fra-2 is up-regulated after cocaine administration, and this effect is prevented by the sigma-1 receptor antagonist BD1063 [1-[2-(3,4-dichlorophenyl)ethyl]-4-methylpiperazine]. In the present study, the effects of cocaine and BD1063 on the expression of six fos and jun genes were evaluated in mouse brains using cDNA microarrays. Several of these genes were altered by cocaine, but only the alteration in fra-2 was prevented by BD1063. The time courses of fra-2 and sigma-1 receptor gene and protein expression in different brain regions were also determined. Cocaine up-regulated fra-2, which was followed by a later up-regulation of sigma-1 receptors. The cocaine-induced up-regulation of fra-2 and sigma-1 receptor genes and proteins were detected in whole brain, striatum, and cortex, but not in cerebellum. All of these cocaine-induced effects were prevented by BD1063. The interaction between cocaine, fra-2, and sigma-1 receptors involves brain regions that are established components of the neural circuit for reward, suggesting that they may contribute to the enduring changes that underlie the cellular basis of drug abuse.

Novel sigma receptor ligands attenuate the locomotor stimulatory effects of cocaine.[Pubmed:9988120]

Eur J Pharmacol. 1999 Jan 15;365(1):35-8.

Cocaine interacts with sigma receptors, suggesting that these sites are important for many of its behavioral effects. Therefore, two novel sigma receptor ligands, BD1008 (N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine) and BD1063 (1-[2-(3,4-dichlorophenyl)ethyl]-4-methylpiperazine), were evaluated for their ability to attenuate cocaine-induced locomotor activity. Receptor binding studies showed that BD1008 and BD1063 have nanomolar affinities for sigma1 and sigma2 sites, but a 250-fold or lower affinity for nine other receptors, making them among the most selective sigma receptor ligands identified. In behavioral studies, pretreatment of mice with BD1008 or BD1063 produced a two-fold increase in the ED50 for the locomotor stimulatory effects of cocaine. These results suggest that sigma receptors are involved in the behavioral effects of cocaine.

Characterization of two novel sigma receptor ligands: antidystonic effects in rats suggest sigma receptor antagonism.[Pubmed:8566098]

Eur J Pharmacol. 1995 Jul 14;280(3):301-10.

The novel sigma receptor ligands, N(-)[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine (BD1047) and 1(-)[2-(3,4-dichlorophenyl)ethyl]-4-methylpiperazine (BD1063), were characterized in rats using binding assays and behavioral studies. In radioligand binding studies, the novel ligands showed marked selectivity for sigma binding sites, generally having a 100-fold or better affinity for sigma sites compared to nine other tested receptors (opiate, phencyclidine, muscarinic, dopamine, alpha 1-, alpha 2-, beta-adrenoceptor, 5-HT1, 5-HT2); the only exception was the affinity of BD1047 for beta-adrenoceptors. Competition assays further revealed that the drugs interacted with both sigma 1 and sigma 2 binding sites. Although both drugs had preferential affinities for sigma 1 sites, BD1047 exhibited a higher affinity for sigma 2 sites than BD1063. In behavioral studies, BD1047 and BD1063 had no effects on their own when unilaterally microinjected into the red nucleus of rats, but both compounds attenuated the dystonia produced by the high affinity sigma ligands, di-o-tolylguanidine (DTG) and haloperidol. BD1047 and BD1063 dose-dependently attenuated the dystonia produced by DTG, suggesting a receptor-mediated mechanism, and the dose curve for DTG was shifted to the right in the presence of the novel ligands. BD1047 and BD1063 appear to act as antagonists at sigma sites and may represent promising new tools for probing other functional effects associated with sigma binding sites.