BD 1008 dihydrobromide

BD 1008 dihydrobromide is a potent and selective ligand for σ-receptor with Ki values of 2 and 8 nM for σ-1 receptor and σ-2 receptor, respectively [1].

σ-receptor is a type of opioid receptor. There are two subtypes of σ-receptor: σ-1 and σ-2 [2].

BD 1008 dihydrobromide is a potent and selective σ-receptor ligand. BD1008 showed high affinity to sites labeled by 4-[125I]PEMP with Ki value of 5.06 nM in guinea pig brain membranes. In MCF-7 breast cancer and melanoma (A375) cells, 4-[125I]PEMP inhibited the binding of BD1008 with Ki value of 11 nM in a dose-dependent way [2]. In Xenopus oocytes coexpressed N-methyl-D-aspartate (NMDA) receptor (NR) 1a with either NR2A, 2B or 2C, BD1008 inhibited NMDA-activated membrane current responses with IC50 values of 62, 18 and 120 μM for NR1a/2A, NR1a/2B and NR1a/2C respectively, which were due to direct effects on the receptor channel complex [3].

In mice, BD1008 (1 mg/kg) inhibited cocaine-induced locomotor activity with ED50 value increased from 6.50 mg/kg to 11.19 mg/kg [1].

References:
[1].  McCracken KA, Bowen WD, Matsumoto RR. Novel sigma receptor ligands attenuate the locomotor stimulatory effects of cocaine. Eur J Pharmacol, 1999, 365(1): 35-38.
[2].  John CS, Gulden ME, Vilner BJ, et al. Synthesis, in vitro validation and in vivo pharmacokinetics of [125I]N-[2-(4-iodophenyl)ethyl]-N-methyl-2-(1-piperidinyl) ethylamine: a high-affinity ligand for imaging sigma receptor positive tumors. Nucl Med Biol, 1996, 23(6): 761-766.
[3].  Whittemore ER, Ilyin VI, Woodward RM. Antagonism of N-methyl-D-aspartate receptors by sigma site ligands: potency, subtype-selectivity and mechanisms of inhibition. J Pharmacol Exp Ther, 1997, 282(1): 326-338.

Antagonism of N-methyl-D-aspartate receptors by sigma site ligands: potency, subtype-selectivity and mechanisms of inhibition.[Pubmed:9223571]

J Pharmacol Exp Ther. 1997 Jul;282(1):326-38.

Recent studies propose that sigma site ligands antagonize N-methyl-D-aspartate (NMDA) receptors by either direct, or indirect mechanisms of inhibition. To investigate this question further we used electrical recordings to assay actions of seventeen structurally diverse sigma site ligands on three diheteromeric subunit combinations of cloned rat NMDA receptors expressed in Xenopus oocytes: NR1a coexpressed with either NR2A, 2B or 2C. The sigma site ligands had a wide range of potency for antagonizing NMDA receptor currents. Steady-state IC50 values ranged between approximately 0.1 to >100 microM. In all cases inhibition was non-competitive with respect to glycine and glutamate. Five structurally related sigma ligands [eliprodil, haloperidol, ifenprodil, 4-phenyl-1-(4-phenylbutyl)-piperidine and trifluperidol] were strongly selective for NR1a/2B receptors. The other drugs were weakly selective or nonselective inhibitors. There was no correlation between sigma site affinity and potency of NMDA receptor antagonism for any subunit combination. Inhibition of NR1a/2B receptors by the selective antagonists was independent of voltage whereas inhibition by the weakly selective antagonists was voltage dependent. Potency of 10 sigma ligands was cross-checked on NMDA currents in cultured rat cortical neurons. There was close correspondence between the two assay systems. Our results argue that antagonism of NMDA receptor currents by the sigma ligands tested is due to direct effects on the receptor channel complex as opposed to indirect effects mediated by sigma receptors. Inhibition occurs via sites in the NMDA receptor channel pore, or via allosteric modulatory sites associated with the NR2B subunit.

Differentiation of sigma ligand-activated receptor subtypes that modulate NMDA-evoked [3H]-noradrenaline release in rat hippocampal slices.[Pubmed:8872358]

Br J Pharmacol. 1996 Sep;119(1):65-72.

1. It is now widely accepted that there are two classes of sigma (sigma) binding sites, denoted sigma(1) and sigma(2), and recently sigma(3) subtype has been proposed. Selective sigma(1) and sigma(2) receptor agonists are known to modulate the neuronal response to N-methyl-D-aspartate (NMDA) in vivo and in vitro. To identify the site of action of a series of recently synthesised high affinity sigma ligands, the present in vitro series of experiments was carried out on NMDA-evoked [3H]-noradrenaline ([3H]-NA) overflow from preloaded hippocampal slices of the rat. 2. The ligands (+)-cis-N-methyl-N-[2,(3,4-dichlorophenyl) ethyl]-2-(1-pyrrolidinyl) cyclohexylamine (BD-737) and (+)-pentazocine, considered as the prototypic sigma(1) agonists, potentiated the NMDA response from 10 nM to 100 nM. This potentiation faded between 100 nM and 1 microM ligand concentrations. On the other hand, 1,3-di(2-tolyl)guanidine (DTG), a mixed sigma(1)/sigma(2) agonist, at concentrations greater than 100 nM inhibited the NMDA-evoked [3H]-NA release. Spiperone, considered as active on putative sigma(3) receptors, was without effect on the NMDA response, or on the potentiating effect of BD-737. 3. The high affinity sigma antagonists haloperidol and 1[2-(3,4-dichlorophenyl)ethyl]-4-methylpiperazine (BD-1063), inactive by themselves on the NMDA-induced response, at concentrations above 30 nM totally prevented the potentiating effect of (+)-pentazocine (100 nM) as well as the inhibitory effect of DTG (300 nM) on NMDA-evoked [3H]-NA release. Whereas haloperidol and BD-1063, at concentrations < 1 microM, were inactive on the potentiating effect of BD-737 (100 nM). 4. 4-(4-Chlorophenyl)-alpha-4-fluorophenyl-4-hydroxy-1-piperidinebutanol (reduced haloperidol), N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine (BD-1008), inactive by themselves on the NMDA-evoked [3H]-NA release, failed to reverse the effects of (+)-pentazocine and DTG, but at concentrations of 30 nM to 1 microM antagonised the BD-737-induced potentiation of the NMDA response. Conversely, N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]-ethylamine monohydrochloride (NE-100) blocked the effects of (+)-pentazocine as well as those of BD-737, but not those of DTG. 5. The present results provide in vitro functional evidence for a sigma receptor type preferentially sensitive to BD-737, reduced haloperidol, BD-1008 and also to NE-100, that differs from the already identified sigma(1), sigma(2) and sigma(3) sites.

Synthesis, characterization, and biological evaluation of a novel class of N-(arylethyl)-N-alkyl-2-(1-pyrrolidinyl)ethylamines: structural requirements and binding affinity at the sigma receptor.[Pubmed:1310114]

J Med Chem. 1992 Jan;35(1):38-47.

By synthesizing and testing a part-structure, N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine (3), derived from our previously reported high affinity sigma receptor ligands (1S,2R)-(-)-N-[2-(3,4-dichlorophenyl)-ethyl]-N-methyl-2-(1- pyrrolidinyl)cyclohexylamine [(-)-2] and (+)-2, we have identified a novel class of superpotent (subnanomolar affinity) sigma ligands specific for the sigma receptor labeled by [3H]-(+)-3-PPP. When 3 was tested for its capacity to displace [3H]-(+)-3-PPP from guinea pig brain membranes, it exhibited a Ki of 0.34 nM, which is better than either of its parent compounds (-)-2 (Ki = 1.3 nM) and (+)-2 (Ki = 6.0 nM). Other compounds related to 3 such as N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-homopiperidinyl)ethy lamine (19) exhibited Ki = 0.17 nM [( 3H]-(+)-3-PPP). The determinants for high sigma receptor affinity of 3 were examined by manipulation of this structure in a number of different ways. The high efficacy of these compounds for the sigma receptor, their relative chemical simplicity and ease of synthesis, and their high degree of selective identifies N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine (3) and related compounds as a highly promising base for determination of the functional role of sigma receptors as well as the development of novel therapeutic agents.