title: Parallel Synthesis of Hexahydrodiimidazodiazepines Heterocyclic Peptidomimetics and Their in Vitro and in Vivo Activities at μ (MOR), δ (DOR), and κ (KOR) Opioid Receptors.
abstract: In the development of analgesics with mixed-opioid agonist activity, peripherally selective activity is expected to decrease side effects, minimizing respiratory depression and reinforcing properties generating significantly safer analgesic therapeutics. We synthesized diazaheterocyclics from reduced tripeptides. In vitro screening with radioligand competition binding assays demonstrated variable affinity for μ (MOR), δ (DOR), and κ (KOR) opioid receptors across the series, with the diimidazodiazepine 14 (2065-14) displaying good affinity for DOR and KOR. Central (icv), intraperitoneal (ip), or oral (po) administration of 14 produced dose-dependent, opioid-receptor mediated antinociception in the mouse, as determined from a 55 °C warm-water tail-withdrawal assay. Only trace amounts of compound 14 was found in brain up to 90 min later, suggesting poor BBB penetration and possible peripherally restricted activity. Central administration of 14 did not produce locomotor effects, acute antinociceptive tolerance, or conditioned-place preference or aversion. The data suggest these diazaheterocyclic mixed activity opioid receptor agonists may hold potential as new analgesics with fewer liabilities of use.
authors.affiliation: Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port St. Lucie, Florida 34987, United States.
authors.forename: Shainnel O
authors.initials: SO
authors.lastname: Eans
authors.affiliation: Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port St. Lucie, Florida 34987, United States.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Ganno
authors.affiliation: Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port St. Lucie, Florida 34987, United States.
authors.forename: Elisa
authors.initials: E
authors.lastname: Mizrachi
authors.affiliation: Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port St. Lucie, Florida 34987, United States.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Houghten
authors.affiliation: Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port St. Lucie, Florida 34987, United States.
authors.forename: Colette T
authors.initials: CT
authors.lastname: Dooley
authors.affiliation: Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port St. Lucie, Florida 34987, United States.
authors.forename: Jay P
authors.initials: JP
authors.lastname: McLaughlin
authors.affiliation: Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port St. Lucie, Florida 34987, United States.
authors.forename: Adel
authors.initials: A
authors.lastname: Nefzi
mesh_terms: D000701:Analgesics, Opioid / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001381:Azepines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001667:Binding, Competitive; D015195:Drug Design; D004361:Drug Tolerance; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010147:Pain Measurement / Q000187:drug effects; D057786:Peptidomimetics / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000378:metabolism
chemical_list: D000701:Analgesics, Opioid; D001381:Azepines; D007093:Imidazoles; D057786:Peptidomimetics; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; C000601137:compound 2065-14