The Synthesis and Pharmacological Evaluation of Salvinorin A Analogues as Opioid Receptor Probes

Abstract

Kappa opioid (KOP) receptors have been shown to be involved in the control of several abuse related effects of central nervous system stimulants. KOP receptor agonists have been shown to modulate the activity of dopamine neurons and decrease self-administration of cocaine in a variety of species, while KOP receptor antagonists have the potential to be utilized as opioid abuse therapies and in the treatment of relapse. With this in mind, investigations were performed on the novel KOP receptor agonist neoclerodane diterpene salvinorin A. This natural product is the active component of the hallucinogenic mint plant Salvia divinorum and the first non-nitrogenous natural product having high affinity and efficacy at KOP receptors. Salvinorin A contains a furan ring, which in other furan containing natural products such as teucrin A and aflatoxin B1 has been identified to cause hepatotoxicity. In efforts to develop a more desirable pharmacological tool, structural modifications were made to salvinorin A in efforts explore the role of the furan ring in affinity and activity at KOP receptors and to reduce its potential for hepatotoxicity. Several ketone analogues were found to retain affinity at KOP receptors relative to salvinorin A and were versatile intermediates for the synthesis of other analogues. Surprisingly, benzisoxazole 187 was found to have increased affinity for MOP receptors. 2-Furanyl salvinorin A (185) was found to have similar efficacy and activity compared to salvinorin A. In addition, Captisol® was identified as a new vehicle for salvinorin A administration in pharmacological assays to eliminate some of the drawbacks of currently used vehicles. These studies assist with the identification of the pharmacophore of salvinorin A as well as the determination of structure-activity relationships, all of which will increase the potential for identification of novel opioid therapeutics.