Wanda Williams

A comparison of (−)-deoxybenzomorphans devoid of opiate activity with their dextrorotatory phenolic counterparts suggests role of σ2 receptors in motor function

Three novel benzomorphans, (+)-N-benzylnormetazocine, (-)-deoxy-N-benzylnormetazocine, and (-)-deoxypentazocine were tested for their ability to produce circling behavior in rats following intranigral microinjections. Dose studies revealed the following rank order of potency: (-)-deoxypentazocine > (-)-deoxy-N-benzylnormetazocine > (+)-N-benzylnormetazocine. This rank order approximates that for affinities for sigma 2 receptors but not sigma 1 receptors. It is very unlikely that the effects of the (-)-deoxybenzomorphans were mediated by opiate receptors for the following reasons: (1) consistent with the known requirement for the phenolic hydroxyl group for opiate activity, both (-)-deoxy compounds showed very low affinity for opiate receptors; (2) naloxone (4 micrograms) co-administered with (-)-deoxy-N-benzylnormetazocine failed to reduce its efficacy; (3) both (-)-deoxy compounds failed to produce marked analgesic effects in the tail flick test following systemic injections of 20 mg/kg s.c. These finding suggest that sigma 2 receptors mediate the motor effects of sigma ligands in rats.

Ibogaine and its congeners are σ2 receptor-selective ligands with moderate affinity

Abstract Ibogaine (12-methoxyibogamine) exhibited moderate affinity for σ2 sites (Ki = 201 nM) and low affinity for σ1 sites (Ki = 8554 nM), thus showing 43-fold selectivity for σ2 receptors. Tabernanthine (13-methoxyibogamine) and (±)-ibogamine had σ2 Ki = 194 nM and 137 nM, respectively. However, they showed 3- to 5-fold higher σ1 affinity compared to ibogaine, resulting in about 14-fold selectivity for σ2 sites over σ1. A potential ibogaine metabolite, O-des-methyl-ibogaine, had markedly reduced σ2 affinity relative to ibogaine (Ki = 5,226 nM) and also lacked significant affinity for σ1 sites. (±)-Coronaridine ((±)-18-carbomethoxyibogamine) and harmaline (1-methyl-7-methoxy-3,4-dihydro-β-carboline) lacked significant affinity for either σ subtype. Thus, σ2 receptors could play a role in the actions of ibogaine.

N-alkyl substituted analogs of the σ receptor ligand BD1008 and traditional σ receptor ligands affect cocaine-induced convulsions and lethality in mice

Cocaine binds to sigma receptors with comparable affinity to its well-established interaction with dopamine transporters. Previous studies have shown BD1008 (N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine) to have high affinity and selectivity for sigma receptors, and to additionally attenuate the locomotor stimulatory effects of cocaine. Therefore, in the present study, three N-alkyl substituted analogs of BD1008 were characterized in receptor binding and behavioral studies: BD1060 (N-[2-(3,4-dichlorophenyl)ethyl]-2-(1-pyrrolidinyl)ethylamine), BD1067 (N-[2-(3,4-dichlorophenyl)ethyl]-N-ethyl-2-(1-pyrrolidinyl)ethylamine), and BD1052 (N-[2-(3,4-dichlorophenyl)ethyl]-N-allyl-2-(1-pyrrolidinyl)ethylamine). Similarly to BD1008, all three analogs exhibited high affinity and selectivity for sigma receptors. In behavioral studies, BD1008, BD1060 or BD1067 attenuated cocaine-induced convulsions and lethality in Swiss Webster mice. The protective effects appear to be mediated through sigma receptor antagonism because traditional sigma receptor antagonists with high to moderate affinity for these receptors also attenuated the behavioral toxicity of cocaine. In contrast, traditional and novel sigma receptor agonists such as di-o-tolylguanidine and BD1052 worsened the behavioral toxicity of cocaine. To further characterize the actions of the N-alkyl substituted compounds, they were microinjected into the rat red nucleus, a functional assay of sigma receptor activity, where they produced agonist vs. antagonist actions that were consistent with their effects on cocaine-induced behaviors. Together, the data demonstrate that BD1008, BD1060 or BD1067 can attenuate the behavioral toxicity of cocaine, most likely through functional antagonism of sigma receptors.

N-Arylalkylpiperidines as high-affinity sigma-1 and sigma-2 receptor ligands: Phenylpropylamines as potential leads for selective sigma-2 agents

To delineate the differences between the structural requirements necessary for recognition at sigma-1 and sigma-2 receptors, a range of phenethyl- and phenylpropylpiperidines were evaluated in binding assays. Phenethylpiperidines were found to favor sigma-1 receptors, whereas phenylpropylpiperidines tend to favor sigma-2 receptors. It appears that phenylpropylamine is a potential pharmacophore for selective sigma-2 ligands.

1,4-dibenzylpiperazines possess anticocaine activity.

N,N-dibenzylpiperazines have high affinity for sigma receptors, and we aimed to increase their anticocaine activity by introducing substituents known to enhance such activity in other sigma ligands. Ligands with high affinity for sigma-1 receptors resulted, but their activity in attenuating cocaine-induced convulsions did not correlate with sigma-1 binding affinity, and may be more closely related to their sigma-2 binding affinities.

A sigma-1 receptor selective analogue of BD1008. A potential substitute for (+)-opioids in sigma receptor binding assays.

A simple, achiral monoamine sigma-1 (sigma1) receptor selective ligand (sigma2Ki/sigma1Ki>2000) is described, which could replace the chiral (+)-pentazocine or dextrallorphan as a sigma1 masking agent in sigma2 binding assays.

The role of novel ligands in the biological characterization of sigma receptors

Publisher Summary This chapter discusses the role of novel ligands in the biological characterization of sigma receptors. Investigation of the physiological and pharmacological role of sigma receptors is a relatively new area that has been facilitated by the development of high affinity and selective sigma receptor ligands including putative agonists and antagonists. Many different classes of drugs, ranging from steroids such as progesterone to neuroleptics such as haloperidol, exhibit high affinity for sigma receptors. This binding activity of the neuroleptic drugs suggested that sigma receptors may be responsible, at least in part, for the motor side-effects of these drugs. Sigma receptor research has been greatly facilitated by the development of chemical tools ranging from antagonists that allow the probing of sigma receptor function to PET scanning ligands, which have allowed visualization of sigma receptors in mammalian brain.