title: The effects of herkinorin, the first mu-selective ligand from a salvinorin A-derived scaffold, in a neuroendocrine biomarker assay in nonhuman primates.
abstract: Herkinorin is the first mu-opioid receptor-selective ligand from the salvinorin A diterpenoid scaffold. Herkinorin has relative mu > kappa > delta binding selectivity, and it can act as an agonist at both mu- and kappa-receptors, in vitro. These studies were the first in vivo evaluation of the effects of herkinorin in nonhuman primates, using prolactin release, a neuroendocrine biomarker assay that is responsive to both mu- and kappa-agonists, as well as to compounds with limited ability to cross the blood-brain barrier. In cumulative dosing studies (0.01-0.32 mg/kg i.v.), herkinorin produced only small effects in gonadally intact males (n = 4), but a more robust effect in females (n = 4). Time course studies with herkinorin (0.32 mg/kg) confirmed this greater effectiveness in females and revealed a fast onset after i.v. administration (e.g., by 5-15 min). Antagonism experiments with different doses of nalmefene (0.01 and 0.1 mg/kg) caused dose-dependent and complete prevention of the effect of herkinorin in females. This is consistent with a principal mu-agonist effect of herkinorin, with likely partial contribution by kappa-agonist effects. The peripherally selective antagonist quaternary naltrexone (1 mg/kg s.c.) caused approximately 70% reduction in the peak effect of herkinorin (0.32 mg/kg) in females, indicating that this effect of herkinorin is prominently mediated outside the blood-brain barrier.
authors.affiliation: The Rockefeller University, Box 171, 1230 York Ave., New York, NY 10065, USA. butelme@rockefeller.edu
authors.forename: Eduardo R
authors.initials: ER
authors.lastname: Butelman
authors.forename: Szymon
authors.initials: S
authors.lastname: Rus
authors.forename: Denise S
authors.initials: DS
authors.lastname: Simpson
authors.forename: Angela
authors.initials: A
authors.lastname: Wolf
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Prisinzano
authors.forename: Mary Jeanne
authors.initials: MJ
authors.lastname: Kreek
mesh_terms: D000818:Animals; D015415:Biomarkers; D045785:Diterpenes, Clerodane / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005663:Furans / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008139:Loperamide / Q000494:pharmacology; D008253:Macaca mulatta; D008297:Male; D009271:Naltrexone / Q000494:pharmacology; D011388:Prolactin / Q000097:blood / Q000378:metabolism*; D011753:Pyrones / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors*
chemical_list: C502982:9-(benzoyloxy)-2-(3-furanyl)dodecahydro-6a,10b-dimethyl-4,10-dioxo-2H-naphtho(2,1-c)pyran-7-carboxylic acid methyl ester; D015415:Biomarkers; D045785:Diterpenes, Clerodane; D005663:Furans; D011753:Pyrones; D017450:Receptors, Opioid, mu; D009271:Naltrexone; D008139:Loperamide; D011388:Prolactin; C090499:salvinorin A