Neuropharmacology of the naturally occurring kappa-opioid hallucinogen salvinorin A

Abstract

Salvia divinorum is a perennial sage native to Oaxaca, Mexico, that has been used traditionally in divination rituals and as a treatment for the "semimagical" disease panzón de borrego. Because of the intense "out-of-body" experiences reported after inhalation of the pyrolized smoke, S. divinorum has been gaining popularity as a recreational hallucinogen, and the United States and several other countries have regulated its use. Early studies isolated the neoclerodane diterpene salvinorin A as the principal psychoactive constituent responsible for these hallucinogenic effects. Since the finding that salvinorin A exerts its potent psychotropic actions through the activation of KOP receptors, there has been much interest in elucidating the underlying mechanisms behind its effects. These effects are particularly remarkable, because 1) salvinorin A is the first reported non-nitrogenous opioid receptor agonist, and 2) its effects are not mediated by the 5-HT(2A) receptor, the classic target of hallucinogens such as lysergic acid diethylamide and mescaline. Rigorous investigation into the structural features of salvinorin A responsible for opioid receptor affinity and selectivity has produced numerous receptor probes, affinity labels, and tools for evaluating the biological processes responsible for its observed psychological effects. Salvinorin A has therapeutic potential as a treatment for pain, mood and personality disorders, substance abuse, and gastrointestinal disturbances, and suggests that nonalkaloids are potential scaffolds for drug development for aminergic G-protein coupled receptors.

Fig. 1.

Chemical structures of salvinorins A (1) and B (2) and ligands with activity at 5-HT (LSD, DMT), NMDA (ketamine), MOP (morphine), and KOP (ketocyclazocine, U50,488) receptors.

Fig. 2.

Chemical structures of naturally occurring neoclerodane diterpenes isolated from S. divinorum (3–22).

Fig. 3.

Hydrolysis products of salvinorin A. [Adapted from Tsujikawa K, Kuwayama K, Miyaguchi H, Kanamori T, Iwata YT, and Inoue H (2009) In vitro stability and metabolism of salvinorin A in rat plasma. Xenobiotica 39:391–398. Copyright © 2009 Informa Medical and Pharmaceutical Science. Used with permission.]

Fig. 4.

Pyrrolysis products of the smoke of salvinorin A (23–29) and S. divinorum (30).

Fig. 5.

Analogs of salvinorin A derivatized at the C-2 position.

Fig. 6.

C-2 epimeric derivatives of salvinorin A.

Fig. 7.

Derivatives of salvinorin A with modifications to the trans-decalin ring system.

Fig. 8.

Furan ring modified analogs of salvinorin A.

Fig. 9.

C-17 des-furyl homologated analogs of salvinorin A.

Fig. 10.

General SAR for salvinorin A activity at KOP receptors. [Adapted from Prisinzano TE and Rothman RB (2008) Salvinorin A analogs as probes in opioid pharmacology. Chem Rev 108:1732–1743. Copyright © 2008 The American Chemical Society. Used with permission.]

Fig. 11.

Graphical representations of the human KOP receptor. A, amino acid sequence alignments for TM II and the EL II of human and rat KOP receptor (hKOR and rKOR, respectively), human MOP receptor (hMOR), and human and mouse DOP receptor (hDOR and mDOR, respectively). B, molecular models of KOP receptor before rotation (green) and after rotation (orange) with salvinorin A docked and energy minimized in both receptors. [Reprinted from Vortherms TA, Mosier PD, Westkaemper RB, and Roth BL (2007) Differential helical orientations among related G protein-coupled receptors provide a novel mechanism for selectivity. Studies with salvinorin A and the kappa-opioid receptor. J Biol Chem 282:3146–3156. Copyright © 2007 The American Society for Biochemistry and Molecular Biology. Used with permission.]

Fig. 12.

Mechanism of covalent receptor modification by KOP receptor probe, 234.

Fig. 13.

Proposed binding modes between salvinorin A and key residues within the KOP receptor. A, Roth et al. (2002). B, Yan et al. (2005). C, Kane et al. (2006). D, Singh et al. (2006).