RESUMO
Though efficacious in managing chronic, severe pain, opioid analgesics are accompanied by significant adverse effects including constipation, tolerance, dependence, and respiratory depression. The life-threatening risks associated with µ opioid receptor agonist-based analgesics challenges their use in clinic. A rational approach to combatting these adverse effects is to develop agents that incorporate activity at a second pharmacologic target in addition to µ opioid receptor activation. The promise of such bivalent or bifunctional ligands is the development of an analgesic with an improved side effect profile. In this review, we highlight ongoing efforts in the development of bivalent and bifunctional analgesics that combine µ agonism with efficacy at κ and δ opioid receptors, the nociceptin opioid peptide (NOP) receptor, σ receptors, and cannabinoid receptors. Several examples of bifunctional analgesics in preclinical and clinical development are highlighted, as are strategies being employed toward the rational design of novel agents.
Assuntos
Dor Crônica , Receptores Opioides , Humanos , Analgésicos/efeitos adversos , Analgésicos Opioides/efeitos adversos , Manejo da Dor , Receptor de Nociceptina , LigantesRESUMO
The resorcinol-terpene phytocannabinoid template is a privileged scaffold for the development of diverse therapeutics targeting the endocannabinoid system. Axially chiral cannabinols (axCBNs) are unnatural cannabinols (CBNs) that bear an additional C10 substituent, which twists the cannabinol biaryl framework out of planarity creating an axis of chirality. This unique structural modification is hypothesized to enhance both the physical and biological properties of cannabinoid ligands, thus ushering in the next generation of endocannabinoid system chemical probes and cannabinoid-inspired leads for drug development. In this full report, we describe the philosophy guiding the design of axCBNs as well as several synthetic strategies for their construction. We also introduce a second class of axially chiral cannabinoids inspired by cannabidiol (CBD), termed axially chiral cannabidiols (axCBDs). Finally, we provide an analysis of axially chiral cannabinoid (axCannabinoid) atropisomerism, which spans two classes (class 1 and 3 atropisomers), and provide first evidence that axCannabinoids retainâand in some cases, strengthenâaffinity and functional activity at cannabinoid receptors. Together, these findings present a promising new direction for the design of novel cannabinoid ligands for drug discovery and exploration of the complex endocannabinoid system.