Development of potent μ and δ opioid agonists with high lipophilicity.
An SAR study on the Dmt-substituted enkephalin-like tetrapeptide with a N-phenyl-N-piperidin-4-ylpropionamide moiety at the C-terminal was performed and has resulted in highly potent ligands at μ and δ opioid receptors. In general, ligands with the substitution of D-Nle(2) and halogenation of the aromatic ring of Phe(4) showed highly increased opioid activities. Ligand 6 with good biological activities in vitro demonstrated potent in vivo antihyperalgesic and antiallodynic effects in the tail-flick assay.
Department of Chemistry and Biochemistry, University of Arizona, Tucson, Arizona 85721, United States.
Yeon Sun
YS
Lee
Vinod
V
Kulkarani
Scott M
SM
Cowell
Shou-wu
SW
Ma
Peg
P
Davis
Katherine E
KE
Hanlon
Todd W
TW
Vanderah
Josephine
J
Lai
Frank
F
Porreca
Ruben
R
Vardanyan
Victor J
VJ
Hruby
D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D002463:Cell Membrane Permeability; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D051379:Mice; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D009437:Neuralgia / Q000188:drug therapy; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011422:Propionates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017465:Receptors, Opioid, delta / Q000819:agonists*; D017450:Receptors, Opioid, mu / Q000819:agonists*; D013329:Structure-Activity Relationship; D014649:Vas Deferens / Q000187:drug effects / Q000502:physiology
D000577:Amides; D000701:Analgesics, Opioid; D008024:Ligands; D009842:Oligopeptides; D010880:Piperidines; D011422:Propionates; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu