The effects of herkinorin, the first {micro}-selective ligand from a salvinorin A- derived scaffold, in a neuroendocrine biomarker assay in non-human primates. The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] Journal article | | Title | The effects of herkinorin, the first {micro}-selective ligand from a salvinorin A- derived scaffold, in a neuroendocrine biomarker assay in non-human primates. | | Author(s) | Butelman ER, Rus S, Simpson DS, Wolf AK, Prisinzano TE, Kreek MJ | | Institution | The Rockefeller University. | | Source | J Pharmacol Exp Ther 2008 Jul 1. | | Abstract | Herkinorin is the first micro-opioid receptor (MOP-r) selective ligand from the salvinorin A diterpenoid scaffold. Herkinorin has relative micro>kappa>delta binding selectivity, and can act as an agonist at both micro- and kappa-receptors, in vitro. These studies were the first in vivo evaluation of herkinorin's effects in non-human primates, using prolactin release, a neuroendocrine biomarker assay that is responsive to both micro- 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 herkinorin's effect in females. This is consistent with a principal micro-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 this effect of herkinorin is prominently mediated outside the blood-brain barrier. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 18593955 |
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