Sanju Narayanan

Sigma receptor agonists: Receptor binding and effects on mesolimbic dopamine neurotransmission assessed by microdialysis

BACKGROUND Subtypes of sigma (σ) receptors, σ₁ and σ₂, can be pharmacologically distinguished, and each may be involved in substance-abuse disorders. σ-Receptor antagonists block cocaine place conditioning and σ-receptor agonists are self-administered in rats that previously self-administered cocaine. Self-administration of abused drugs has been related to increased dopamine (DA) neurotransmission, however, σ-receptor agonist effects on mesolimbic DA are not fully characterized. METHODS Receptor-binding studies assessed affinities of σ-receptor ligands for σ-receptor subtypes and the DA transporter; effects on DA transmission in the rat nucleus accumbens shell were assessed using in vivo microdialysis. RESULTS Cocaine (.1-1.0 mg/kg intravenous [IV]), the nonselective σ(½)-receptor agonist DTG (1.0-5.6 mg/kg IV), and the selective σ₁-receptor agonist PRE-084 (.32-10 mg/kg IV) dose-dependently increased DA to ∼275%, ∼150%, and ∼160% maxima, respectively. DTG-induced stimulation of DA was antagonized by the nonselective σ(½)-receptor antagonist BD 1008 (10 mg/kg intraperitoneal [IP]) and the preferential σ₂-receptor antagonist SN 79 (1-3 mg/kg IP), but not by the preferential σ₁-receptor antagonist, BD 1063 (10-30 mg/kg IP). Neither PRE-084 nor cocaine was antagonized by BD 1063 or BD 1008. CONCLUSIONS σ-Receptor agonists stimulated DA in a brain area critical for reinforcing effects of cocaine. DTG effects on DA appear to be mediated by σ₂-receptors rather than σ₁-receptors. However, DA stimulation by cocaine or PRE-084 does not likely involve σ-receptors. The relatively low potency on DA transmission of the selective σ₁-receptor agonist, PRE-084, and its previously reported potent reinforcing effects, suggest a dopamine-independent reinforcing pathway that may contribute to substance-abuse disorders.

Conversion of a highly selective sigma-1 receptor-ligand to sigma-2 receptor preferring ligands with anticocaine activity

Cocaines toxicity can be mitigated by blocking its interaction with sigma-1 receptors. The involvement of sigma-2 receptors remains unclear. To investigate their potential role, we have designed compounds through a convergent synthesis utilizing a highly selective sigma-1 ligand and elements of a selective sigma-2 ligand. Among the synthesized compounds was produced a subnanomolar sigma-2 ligand with an 11-fold preference over sigma-1 receptors. These compounds may be useful in developing effective pharmacotherapies for cocaine toxicity.

Early development of sigma-receptor ligands

Sigma receptors (σ-1 and σ-2) are non-opioid proteins implicated in the pathophysiology of various neurological disorders and cancer. The σ-1 subtype is a chaperon protein widely distributed in the CNS and peripheral tissues. These receptors are involved in the modulation of K(+)- and Ca(2+)-dependent signaling cascades at the endoplasmic reticulum and modulation of neurotransmitter release. σ-1 receptors are emerging targets for the treatment of neurophychiatric diseases (schizophrenia and depression) and cocaine addiction. σ-2 receptors are lipid raft proteins. They are highly expressed on many tumor cells and hence considered potential targets for anticancer drugs. σ receptors bind to a diverse class of pharmacological compounds like cocaine, methamphetamine, benzomorphans like (±)-pentazocine, (±)-SKF-10,047 and endogenous neurosteroids and sphingolipids. In this review we focus on the early development of σ receptor-specific ligands and radiolabeling agents.

Sigma Receptors and Cocaine Abuse

Sigma receptors have been well documented as a protein target for cocaine and have been shown to be involved in the toxic and stimulant actions of cocaine. Strategies to reduce the access of cocaine to sigma receptors have included antisense oligonucleotides to the sigma-1 receptor protein as well as small molecule ligand with affinity for sigma receptor sites. These results have been encouraging as novel protein targets that can attenuate the actions of cocaine are desperately needed as there are currently no medications approved for treatment of cocaine toxicity or addiction. Many years of research in this area have yet to produce an effective treatment and much focus was on dopamine systems. A flurry of research has been carried out to elucidate the role of sigma receptors in the blockade of cocaine effects but this research has yet to yield a clinical agent. This review summarizes the work to date on the linkage of sigma receptors and the actions of cocaine and the progress that has been made with regard to small molecules. Although there is still a lack of an agent in clinical trials with a sigma receptor mechanism of action, work is progressing and the ligands are becoming more selective for sigma systems and the potential remains high.

Regulation of the Apelinergic System and Its Potential in Cardiovascular Disease: Peptides and Small Molecules as Tools for Discovery.

Apelin peptides and the apelin receptor represent a relatively new therapeutic axis for the potential treatment of cardiovascular disease. Several reports suggest apelin receptor activation with apelin peptides results in cardioprotection as noted through positive ionotropy, angiogenesis, reduction of mean arterial blood pressure, and apoptosis. Considering the potential therapeutic benefit attainable through modulation of the apelinergic system, research is expanding to develop novel therapies that limit the inherent rapid degradation of endogenous apelin peptides and produce metabolically stable small molecule agonists and antagonists to more rigorously interrogate the apelin receptor system. This review details the structure-activity relationships for chemically modified apelin peptides and recent disclosures of small molecule agonists and antagonists and summarizes the peer reviewed and patented literature. Development of metabolically stable ligands of apelin receptor and their effects in various models over the coming years will hopefully lead to establishment of this receptor as a validated target for cardiovascular indications.

Blockade of Cocaine or σ Receptor Agonist Self Administration by Subtype-Selective σ Receptor Antagonists

The identification of sigma receptor (σR) subtypes has been based on radioligand binding and, despite progress with σ1R cellular function, less is known about σR subtype functions in vivo. Recent findings that cocaine self administration experience will trigger σR agonist self administration was used in this study to assess the in vivo receptor subtype specificity of the agonists (+)-pentazocine, PRE-084 [2-(4-morpholinethyl) 1-phenylcyclohexanecarboxylate hydrochloride], and 1,3-di-o-tolylguanidine (DTG) and several novel putative σR antagonists. Radioligand binding studies determined in vitro σR selectivity of the novel compounds, which were subsequently studied for self administration and antagonism of cocaine, (+)-pentazocine, PRE-084, or DTG self administration. Across the dose ranges studied, none of the novel compounds were self administered, nor did they alter cocaine self administration. All compounds blocked DTG self administration, with a subset also blocking (+)-pentazocine and PRE-084 self administration. The most selective of the compounds in binding σ1Rs blocked cocaine self administration when combined with a dopamine transport inhibitor, either methylphenidate or nomifensine. These drug combinations did not decrease rates of responding maintained by food reinforcement. In contrast, the most selective of the compounds in binding σ2Rs had no effect on cocaine self administration in combination with either dopamine transport inhibitor. Thus, these results identify subtype-specific in vivo antagonists, and the utility of σR agonist substitution for cocaine self administration as an assay capable of distinguishing σR subtype selectivity in vivo. These results further suggest that effectiveness of dual σR antagonism and dopamine transport inhibition in blocking cocaine self administration is specific for σ1Rs and further support this dual targeting approach to development of cocaine antagonists.