Salvinorin A analogs and other κ-opioid receptor compounds as treatments for cocaine abuse

Abstract

Acute activation of kappa-opioid receptors produces anti-addictive effects by regulating dopamine levels in the brain. Unfortunately, classic kappa-opioid agonists have undesired side effects such as sedation, aversion, and depression, which restrict their clinical use. Salvinorin A (Sal A), a novel kappa-opioid receptor agonist extracted from the plant Salvia divinorum, has been identified as a potential therapy for drug abuse and addiction. Here, we review the preclinical effects of Sal A in comparison with traditional kappa-opioid agonists and several new analogs. Sal A retains the anti-addictive properties of traditional kappa-opioid receptor agonists with several improvements including reduced side effects. However, the rapid metabolism of Sal A makes it undesirable for clinical development. In an effort to improve the pharmacokinetics and tolerability of this compound, kappa-opioid receptor agonists based on the structure of Sal A have been synthesized. While work in this field is still in progress, several analogs with improved pharmacokinetic profiles have been shown to have anti-addictive effects. While in its infancy, it is clear that these compounds hold promise for the future development of anti-addictive therapeutics.

Keywords: Addiction; Drug abuse; Kappa-opioid receptor; Salvia divinorum; Salvinorin A.

Figure 1. Kappa opioid receptor agonists

Opioid receptor binding ([³H] U69,593) in CHO cells expressing human KOP receptors (Ki ±SD nM). ED₅₀ = effective dose for 50% of maximal response in [³⁵S] GTP-γS binding. Data for EOM SalB, MOM SalB and β-Tetrahydropyran Sal B taken from Prevatt-Smith et al. (2011) and data for Sal A taken from Lozama et al. (2011) (Lozama, Cunningham, Caspers, Douglas, Dersch, Rothman et al., 2011).