22-thiocyanatosalvinorin-a and Pain

Opioid analgesics have been used for thousands of years in the treatment of pain and related disorders, and have become among the most widely prescribed medications. Among opioid analgesics, mu opioid receptor (MOR) agonists are the most commonly used and are indicated for acute and chronic pain management. However, their use results in a plethora of well-described side-effects. From selective delta opioid receptor (DOR) and kappa opioid receptor (KOR) agonists to multitarget MOR/DOR and MOR/KOR ligands, medicinal chemistry provided different approaches aimed at the development of opioid analgesics with an improved pharmacological and tolerability fingerprint. The emergent medicinal chemistry strategy to develop ameliorated opioid analgesics is based upon the concept that functional selectivity for G-protein signalling is necessary for the therapeutic effect, whether β-arrestin recruitment is mainly responsible for the manifestation of side effects, including the development of tolerance after repeated administrations. This review summarises most relevant biased MOR, DOR, KOR and multitarget MOR/DOR ligands synthesised in the last decade and their pharmacological profile in "in vitro" and "in vivo" studies. Such biased ligands could have a significant impact on modern drug discovery and represent a new strategy for the development of better-tolerated drug candidates.

Topics: Analgesics, Opioid; Animals; Dose-Response Relationship, Drug; Humans; Molecular Structure; Pain; Pain Management; Receptors, Opioid, mu; Structure-Activity Relationship

Strong opioid analgesics, including morphine, are the mainstays for treating moderate to severe acute pain and alleviating chronic cancer pain. However, opioid-related adverse effects, including nausea or vomiting, sedation, respiratory depression, constipation, pruritus (itch), analgesic tolerance, and addiction and abuse liability, are problematic. In addition, the use of opioids to relieve chronic noncancer pain is controversial due to the "opioid crisis" characterized by opioid misuse or abuse and escalating unintentional death rates due to respiratory depression. Hence, considerable research internationally has been aimed at the "Holy Grail" of the opioid analgesic field, namely the discovery of novel and safer opioid analgesics with improved opioid-related adverse effects. In this Perspective, medicinal chemistry strategies are addressed, where structurally diverse nonmorphinan-based opioid ligands derived from natural sources were deployed as lead molecules. The current state of play, clinical or experimental status, and novel opioid ligand discovery approaches are elaborated in the context of retaining analgesia with improved safety and reduced adverse effects, especially addiction liability.

Topics: Analgesics, Opioid; Animals; Biological Products; Cell Line, Tumor; Chemistry, Pharmaceutical; Drug Discovery; Humans; Ligands; Pain; Peptides; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu