| Autor: |
McLaughlin JP; Department of Pharmacodynamics, University of Florida, Gainesville, FL 32610, USA., Rayala R; Center for Translational Science, Florida International University, Port St. Lucie, FL 34987, USA., Bunnell AJ; Center for Translational Science, Florida International University, Port St. Lucie, FL 34987, USA., Tantak MP; Center for Translational Science, Florida International University, Port St. Lucie, FL 34987, USA., Eans SO; Department of Pharmacodynamics, University of Florida, Gainesville, FL 32610, USA., Nefzi K; Department of Pharmacodynamics, University of Florida, Gainesville, FL 32610, USA., Ganno ML; Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port St. Lucie, FL 34987, USA., Dooley CT; Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port St. Lucie, FL 34987, USA., Nefzi A; Center for Translational Science, Florida International University, Port St. Lucie, FL 34987, USA. |
| Abstrakt: |
The design and development of analgesics with mixed-opioid receptor interactions has been reported to decrease side effects, minimizing respiratory depression and reinforcing properties to generate safer analgesic therapeutics. We synthesized bis-cyclic guanidine heterocyclic peptidomimetics from reduced tripeptides. In vitro screening with radioligand competition binding assays demonstrated variable affinity for the mu-opioid receptor (MOR), delta-opioid receptor (DOR), and kappa-opioid receptor (KOR) across the series, with compound 1968-22 displaying good affinity for all three receptors. Central intracerebroventricular (i.c.v.) administration of 1968-22 produced dose-dependent, opioid receptor-mediated antinociception in the mouse 55 °C warm-water tail-withdrawal assay, and 1968-22 also produced significant antinociception up to 80 min after oral administration (10 mg/kg, p.o.). Compound 1968-22 was detected in the brain 5 min after intravenous administration and was shown to be stable in the blood for at least 30 min. Central administration of 1968-22 did not produce significant respiratory depression, locomotor effects or conditioned place preference or aversion. The data suggest these bis-cyclic guanidine heterocyclic peptidomimetics with multifunctional opioid receptor activity may hold potential as new analgesics with fewer liabilities of use. |
