title: Synthesis and Opioid Activity of Tyr1-ψ[(Z)CF=CH]-Gly2and Tyr1-ψ[(S)/(R)-CF3CH-NH]-Gly2Leu-enkephalin Fluorinated Peptidomimetics.
abstract: We describe the design, synthesis, and opioid activity of fluoroalkene (Tyr1-ψ[(Z)CF=CH]-Gly2) and trifluoroethylamine (Tyr1-ψ[(S)/(R)-CF3CH-NH]-Gly2) analogues of the endogenous opioid neuropeptide, Leu-enkephalin. The fluoroalkene peptidomimetic exhibited low nanomolar functional activity (5.0±2 nm and 60±15 nm for δ- and μ-opioid receptors, respectively) with a μ/δ-selectivity ratio that mimics that of the natural peptide. However, the trifluoroethylamine peptidomimetics, irrespective of stereochemistry, did not activate the opioid receptors, which suggest that bulky CF3substituents are not tolerated at this position.
authors.affiliation: Department of Medicinal Chemistry, The University of Kansas, 1251 Wescoe Hall Drive, Lawrence, Kansas, 66045, USA.
authors.forename: Somnath Narayan
authors.initials: SN
authors.lastname: Karad
authors.affiliation: Department of Medicinal Chemistry, The University of Kansas, 1251 Wescoe Hall Drive, Lawrence, Kansas, 66045, USA.
authors.forename: Mohan
authors.initials: M
authors.lastname: Pal
authors.affiliation: Department of Medicinal Chemistry, The University of Kansas, 1251 Wescoe Hall Drive, Lawrence, Kansas, 66045, USA.
authors.forename: Rachel S
authors.initials: RS
authors.lastname: Crowley
authors.affiliation: Department of Medicinal Chemistry, The University of Kansas, 1251 Wescoe Hall Drive, Lawrence, Kansas, 66045, USA.
authors.forename: Thomas E
authors.identifier: 0000-0002-0649-8052
authors.initials: TE
authors.lastname: Prisinzano
authors.affiliation: Department of Medicinal Chemistry, The University of Kansas, 1251 Wescoe Hall Drive, Lawrence, Kansas, 66045, USA.
authors.forename: Ryan A
authors.identifier: 0000-0002-8724-1098
authors.initials: RA
authors.lastname: Altman
mesh_terms: D000701:Analgesics, Opioid / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D003412:Cricetulus; D004743:Enkephalin, Leucine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000138:chemical synthesis / Q000494:pharmacology*; D057786:Peptidomimetics / Q000138:chemical synthesis / Q000494:pharmacology*; D011957:Receptors, Opioid / Q000819:agonists; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000701:Analgesics, Opioid; D006845:Hydrocarbons, Fluorinated; D057786:Peptidomimetics; D011957:Receptors, Opioid; D004743:Enkephalin, Leucine
keywords: amide bonds; enkephalin; fluorine; opioids; peptidomimetics