Design and synthesis of novel bivalent ligands (MOR and DOR) by conjugation of enkephalin analogues with 4-anilidopiperidine derivatives.
We describe the design and synthesis of novel bivalent ligands based on the conjugation of 4-anilidopiperidine derivatives with enkephalin analogues. The design of non-peptide analogues is explored with 5-amino substituted (tetrahydronaphthalen-2yl) methyl containing 4-anilidopiperidine derivatives, while non-peptide-peptide ligands are explored by conjugating the C-terminus of enkephalin analogues (H-Xxx-DAla-Gly-Phe-OH) to the amino group of 4-anilidopiperidine small molecule derivatives with and without a linker. These novel bivalent ligands are evaluated for biological activities at μ and δ opioid receptors. They exhibit very good affinities at μ and δ opioid receptors, and potent agonist activities in MVD and GPI assays. Among these the lead bivalent ligand 17 showed excellent binding affinities (0.1 nM and 0.5 nM) at μ and δ opioid receptors respectively, and was found to have very potent agonist activities in MVD (56 ± 5.9 nM) and GPI (4.6 ± 1.9 nM) assays. In vivo the lead bivalent ligand 17 exhibited a short duration of action (<15 min) comparable to 4-anilidopiperidine derivatives, and moderate analgesic activity. The ligand 17 has limited application against acute pain but may have utility in settings where a highly reversible analgesic is required.
Department of Chemistry and Biochemistry, University of Arizona, 1306 E. University Boulevard, Tucson, AZ 85721, USA.
Srinivas
S
Deekonda
Department of Chemistry and Biochemistry, University of Arizona, 1306 E. University Boulevard, Tucson, AZ 85721, USA.
Lauren
L
Wugalter
Department of Pharmacology, University of Arizona, Tucson, AZ 85724, USA.
David
D
Rankin
Department of Pharmacology, University of Arizona, Tucson, AZ 85724, USA.
Tally M
TM
Largent-Milnes
Department of Pharmacology, University of Arizona, Tucson, AZ 85724, USA.
Peg
P
Davis
Department of Pharmacology, University of Arizona, Tucson, AZ 85724, USA.
Yue
Y
Wang
Department of Pharmacology, University of Arizona, Tucson, AZ 85724, USA.
Neemah M
NM
Bassirirad
Department of Pharmacology, University of Arizona, Tucson, AZ 85724, USA.
Josephine
J
Lai
Department of Chemistry and Biochemistry, University of Arizona, 1306 E. University Boulevard, Tucson, AZ 85721, USA.
Vinod
V
Kulkarni
Department of Pharmacology, University of Arizona, Tucson, AZ 85724, USA.
Todd W
TW
Vanderah
Department of Pharmacology, University of Arizona, Tucson, AZ 85724, USA.
Frank
F
Porreca
Department of Chemistry and Biochemistry, University of Arizona, 1306 E. University Boulevard, Tucson, AZ 85721, USA. Electronic address: hruby@email.arizona.edu.
Victor J
VJ
Hruby
D000700:Analgesics / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004745:Enkephalins / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D006168:Guinea Pigs; D008024:Ligands; D051379:Mice; D008968:Molecular Conformation; D009119:Muscle Contraction / Q000187:drug effects*; D010147:Pain Measurement / Q000187:drug effects; D017288:Pain Threshold / Q000187:drug effects*; D010880:Piperidines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000819:agonists*; D013329:Structure-Activity Relationship
C000608309:4-anilidopiperidine; D000700:Analgesics; D004745:Enkephalins; D008024:Ligands; D010880:Piperidines; D011957:Receptors, Opioid
Bivalent ligands; Enkephalins; Opioid receptors; Opioids