Synthesis and biological evaluation of new opioid agonist and neurokinin-1 antagonist bivalent ligands.

TitleSynthesis and biological evaluation of new opioid agonist and neurokinin-1 antagonist bivalent ligands.
Publication TypeJournal Article
Year of Publication2011
AuthorsVardanyan R, Kumirov VK, Nichol GS, Davis P, Liktor-Busa E, Rankin D, Varga E, Vanderah T, Porreca F, Lai J, Hruby VJ
JournalBioorg Med Chem
Volume19
Issue20
Pagination6135-42
Date Published2011 Oct 15
ISSN1464-3391
KeywordsAnalgesics, Opioid, Animals, Binding Sites, Drug Design, Guinea Pigs, Humans, Ligands, Male, Mice, Mice, Inbred ICR, Neurokinin-1 Receptor Antagonists, Receptors, Neurokinin-1
Abstract

Newly designed bivalent ligands-opioid agonist/NK1-antagonists have been synthesized. The synthesis of new starting materials-carboxy-derivatives of Fentanyl (1a-1c) was developed. These products have been transformed to 'isoimidium perchlorates' (2a-c). The new isoimidium perchlorates have been successfully implemented in nucleophilic addition reactions, with l-tryptophan 3,5-bis(trifluoromethyl)benzyl ester to give the target compounds-amides (3a-c). Perchlorates (2a-c) successfully undergo reactions with other nucleophiles such as alcohols, amines or hydrazines. The obtained compound 3b exhibited μ-opioid agonist activity and NK1-antagonist activity and may serve as a useful lead compound for the further design of a new series of opioid agonist/NK1-antagonist compounds.
DOI10.1016/j.bmc.2011.08.027
Alternate JournalBioorg. Med. Chem.
PubMed ID21925887
PubMed Central IDPMC4137774
Grant ListDA 06284 / DA / NIDA NIH HHS / United States
DA 06789 / DA / NIDA NIH HHS / United States
DA 13449 / DA / NIDA NIH HHS / United States
P01 DA006284 / DA / NIDA NIH HHS / United States
R01 DA013449 / DA / NIDA NIH HHS / United States
Faculty Member Reference: 
Peg Davis
Victor Hruby, Ph.D.
Josephine Lai , Ph.D.
Frank Porreca, PhD
Todd Vanderah, PhD
Eva Varga, Ph.D.