Therapeutic Potential of Salvinorin A and Its Analogues in Various Neurological Disorders

Summary

Salvinorin A, the active component of the hallucinogenic plant Salvia divinorum, is a potent and highly selective kappa opioid receptor (KOR) agonist with a unique chemical structure lacking nitrogen, unlike all classic opioid receptor ligands. Its fast metabolism via hydrolysis to inactive salvinorin B results in a short duration of action, but a single dose induces rapid and robust changes in neural activity and connectivity in disease-related circuits. These neurophysiological effects may explain its rapid and durable therapeutic effects in difficult-to-treat neuropsychiatric disorders. The compound also serves as a valuable backbone for developing novel KOR-targeting drugs.

Study at a glance

Abstract

While the hallucinogenic plant Salvia divinorum has been safely consumed by humans for centuries for religious or recreational purposes without long-term side effects, its active component, salvinorin A, and molecular mechanism of action were not known until recently [1]. Notably, salvinorin A is a potent kappa opioid receptor (KOR) agonist that is highly selective for KOR without significant interactions with any other receptors [2]. Different from classic opioid receptor ligands, which are opiate, this is the first molecule that has no nitrogen in its chemical structure but can interact with an opioid receptor with high affinity and potency (Figure 1) [1]. All classic opioid receptor agonists or antagonists have nitrogen in their chemical structures; therefore, it had been hypothesized that nitrogen was essential for a compound to have any opioid receptor activity until salvinorin A was discovered. In addition to its unique chemical structure, salvinorin A has very high selectivity towards KOR. Thus, it has been used as a great tool to study the pure pharmacological effects of KOR agonism. The C2 ester in the chemical structure quickly undergoes hydrolysis to yield the inactive metabolite salvinorin B, resulting in salvinorin A undergoing fast metabolism in the body. Despite its short duration of action, a single dose of salvinorin A, like other classic psychedelics, induces rapid and robust changes in the patterns of neural activity and connectivity in disease-related neuronal circuits. While not fully understood, these neurophysiological effects might explain salvinorin A’s rapid and durable therapeutic effects in neuropsychiatric disorders that are difficult to treat. Furthermore, the unique chemical structure of salvinorin A provides a useful backbone for chemists to develop novel compounds targeting KOR and other opioid receptors for structure-activity relationships, structure-function analyses, and novel medication design purposes [3,4].