title: [N-allyl-Dmt1]-endomorphins are micro-opioid receptor antagonists lacking inverse agonist properties.
abstract: [N-allyl-Dmt1]-endomorphin-1 and -2 ([N-allyl-Dmt1]-EM-1 and -2) are new selective micro-opioid receptor antagonists obtained by N-alkylation with an allyl group on the amino terminus of 2',6'-dimethyl-L-tyrosine (Dmt) derivatives. To further characterize properties of these compounds, their intrinsic activities were assessed by functional guanosine 5'-O-(3-[35S]thiotriphosphate) binding assays and forskolin-stimulated cyclic AMP accumulation in cell membranes obtained from vehicle, morphine, and ethanol-treated SK-N-SH cells and brain membranes isolated from naive and morphine-dependent mice; their mode of action was compared with naloxone or naltrexone, which both are standard nonspecific opioid-receptor antagonists. [N-allyl-Dmt1]-EM-1 and -2 were neutral antagonists under all of the experimental conditions examined, in contrast to naloxone and naltrexone, which behave as neutral antagonists only in membranes from vehicle-treated cells and mice but act as inverse agonists in membranes from morphine- and ethanol-treated cells as well as morphine-treated mice. Both endomorphin analogs inhibited the naloxone- and naltrexone-elicited withdrawal syndromes from acute morphine dependence in mice. This suggests their potential therapeutic application in the treatment of drug addiction and alcohol abuse without the adverse effects observed with inverse agonist alkaloid-derived compounds that produce severe withdrawal symptoms.
authors.affiliation: Medicinal Chemistry Group, Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, P.O. Box 12233, MD C304, Research Triangle Park, NC 27709, USA. marczake@niehs.nih.gov
authors.forename: Ewa D
authors.initials: ED
authors.lastname: Marczak
authors.forename: Yunden
authors.initials: Y
authors.lastname: Jinsmaa
authors.forename: Tingyou
authors.initials: T
authors.lastname: Li
authors.forename: Sharon D
authors.initials: SD
authors.lastname: Bryant
authors.forename: Yuko
authors.initials: Y
authors.lastname: Tsuda
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Okada
authors.forename: Lawrence H
authors.initials: LH
authors.lastname: Lazarus
mesh_terms: D000701:Analgesics, Opioid / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D008297:Male; D051379:Mice; D009842:Oligopeptides / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D011869:Radioligand Assay; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000037:antagonists & inhibitors*; D013375:Substance Withdrawal Syndrome / Q000209:etiology; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000737:chemistry
chemical_list: D000701:Analgesics, Opioid; D009842:Oligopeptides; D017450:Receptors, Opioid, mu; C105293:endomorphin 1; C076121:2',6'-dimethyltyrosine; D016244:Guanosine 5'-O-(3-Thiotriphosphate); C105294:endomorphin 2; D014443:Tyrosine; D000242:Cyclic AMP