ABSTRACT
Mitragynine (MG) is the most abundant alkaloid component of the psychoactive plant material "kratom", which according to numerous anecdotal reports shows efficacy in self-medication for pain syndromes, depression, anxiety, and substance use disorders. We have developed a synthetic method for selective functionalization of the unexplored C11 position of the MG scaffold (C6 position in indole numbering) via the use of an indole-ethylene glycol adduct and subsequent iridium-catalyzed borylation. Through this work we discover that C11 represents a key locant for fine-tuning opioid receptor signaling efficacy. 7-Hydroxymitragynine (7OH), the parent compound with low efficacy on par with buprenorphine, is transformed to an even lower efficacy agonist by introducing a fluorine substituent in this position (11-F-7OH), as demonstrated in vitro at both mouse and human mu opioid receptors (mMOR/hMOR) and in vivo in mouse analgesia tests. Low efficacy opioid agonists are of high interest as candidates for generating safer opioid medications with mitigated adverse effects.
Subject(s)
Mitragyna/chemistry , Plant Extracts/pharmacology , Receptors, Opioid, mu/agonists , Secologanin Tryptamine Alkaloids/pharmacology , Analgesics/chemistry , Analgesics/pharmacology , Animals , Ethylene Glycol/chemistry , Humans , Mice, Knockout , Models, Chemical , Molecular Structure , Plant Extracts/chemistry , Protein Binding , Receptors, Opioid, mu/genetics , Receptors, Opioid, mu/metabolism , Secologanin Tryptamine Alkaloids/chemistryABSTRACT
Opioid receptor like-1 receptor (ORL(1)) is selective for orphaninFQ/nociceptin (OFQ/N), a peptide linked to stress. Since immunologic stimuli exert stressor-like effects, the neuroendocrine and behavioral effects of the T-cell superantigen staphylococcal enterotoxin A (SEA) were tested in ORL(1)(-/-) and ORL(1)(+/+) wildtype 129S6 mice. Within 2h of SEA challenge both genotypes showed elevated corticosterone, but only wildtypes were elevated after 4h, and had altered hypothalamic CRH mRNA. Although amygdaloid CRH and TNFalpha mRNA was increased by SEA, this did not vary with genotype. Interestingly, gustatory neophobia due to SEA challenge was augmented in ORL(1)(-/-) mice, although object neophobia tested 4days later was abrogated. These results suggest differential requirements for ORL(1) in the mediation of neuroimmune effects exerted at different times after an immune challenge.