Salvinorin A was isolated from the psychoactive plant <i>Salvia divinorum</i>, used in traditional practices in Mexico. Remarkably, salvinorin A was the first nonalkaloid molecule identified as a selective kappa-opioid receptor agonist, showing similar potency to known hallucinogenic drugs such as lysergic acid diethylamide (LSD). The search of salvinorin A analogues rendered the discovery of herkinorin, the first neoclerodane diterpene with µ-opioid receptor (µ-OR) affinity. Experimental studies revealed the differential activation of µ-OR by herkinorin, which selectively promotes the Gi over β-arrestin signaling pathway. This important pharmacological phenomenon is termed functional selectivity or biased agonism, observed in several G-protein coupled receptors (GPCRs). The selective activation of biological signaling pathways promises improved pharmacological profiles. Specifically, biased µ-OR ligands are showing potent analgesia with diminished adverse effects, in contrast to traditional µ-OR analgesics. Interestingly, despite the massive amount of µ-OR agonists currently known, only eight have been reported as biased. Clearly, more µ-OR ligands are yet to be discovered. Natural products (NPs) and their derivatives have long-standing and sustained reputation as the main source of bioactive molecules, being the opiates the most potent analgesics. Our long-term goal is to contribute to the understanding of biased agonism of µ-OR ligands and to enrich their repertoire. In this work, we focused on the screening of NPs as well as chemically diverse databases. First, we prepared a database of the known µ-OR biased ligands (BL-DB) and performed a similarity search against chemical collections publically available. Then, based on previous detailed studies of the molecular recognition process involved, we propose a protein-ligand interaction fingerprint (PLIF) for the further selection of promising hits. Taken together, these findings provide a preliminary framework for the exploration and discovery of biased ligands, according to the insights responsible for their functional selectivity properties and structural features.

Search of biased mu-opioid receptor ligands from nature

256th National Meeting (2018)

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