Development of novel enkephalin analogues that have enhanced opioid activities at both mu and delta opioid receptors.
Enkephalin analogues with a 4-anilidopiperidine scaffold have been designed and synthesized to achieve therapeutic benefit for the treatment of pain due to mixed mu and delta opioid agonist activities. Ligand 16, in which a Dmt-substituted enkephalin-like structure was linked to the N-phenyl-N-piperidin-4-yl propionamide moiety, showed very high binding affinities (0.4 nM) at mu and delta receptors with an increased hydrophobicity (aLogP = 2.96). This novel lead compound was found to have very potent agonist activities in MVD (1.8 nM) and GPI (8.5 nM) assays.
Lee
Yeon Sun
YS
Department of Chemistry, University of Arizona, Tucson, Arizona 85721, USA.
Petrov
Ravil
R
Park
Chad K
CK
Ma
Shou-wu
SW
Davis
Peg
P
Lai
Josephine
J
Porreca
Frank
F
Vardanyan
Ruben
R
Hruby
Victor J
VJ
D000818:Animals; D001667:Binding, Competitive; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D004745:Enkephalins / Q000138:chemical synthesis* / Q000494:pharmacology; D006168:Guinea Pigs; D006801:Humans; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D011869:Radioligand Assay; D051381:Rats; D017465:Receptors, Opioid, delta / Q000819:agonists*; D017450:Receptors, Opioid, mu / Q000819:agonists*; D013329:Structure-Activity Relationship; D014649:Vas Deferens / Q000187:drug effects / Q000502:physiology
D004745:Enkephalins; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu