A Structure–Activity Relationship Study and Combinatorial Synthetic Approach of C-Terminal Modified Bifunctional Peptides That Are δ/μ Opioid Receptor Agonists and Neurokinin 1 Receptor Antagonists
| Autor: | Josephine Lai, Todd W. Vanderah, Peg Davis, Sharif Moye, Tally M. Largent-Milnes, Padma Nair, Henry I. Yamamura, Takashi Yamamoto, Edita Navratilova, Shou Wu Ma, Josef Vagner, Victor J. Hruby, Suneeta Tumati, Frank Porreca |
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| Rok vydání: | 2008 |
| Předmět: |
Male
Agonist medicine.drug_class Stereochemistry Guinea Pigs Receptors Opioid mu Peptide In Vitro Techniques Article Cell Line Mice Radioligand Assay Structure-Activity Relationship Cricetulus Vas Deferens Neurokinin-1 Receptor Antagonists Ileum Opioid receptor Cell Line Tumor Cricetinae Receptors Opioid delta Drug Discovery medicine Animals Combinatorial Chemistry Techniques Humans Structure–activity relationship Receptor chemistry.chemical_classification Chemistry Muscle Smooth Electric Stimulation Rats Opioid Molecular Medicine Pharmacophore μ-opioid receptor Oligopeptides Muscle Contraction medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 51:1369-1376 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm070332f |
| Popis: | A series of bifunctional peptides with opioid agonist and substance P antagonist bioactivities were designed with the concept of overlapping pharmacophores. In this concept, the bifunctional peptides were expected to interact with each receptor separately in the spinal dorsal horn where both the opioid receptors and the NK1 receptors were found to be expressed, to show an enhanced analgesic effect, no opioid-induced tolerance, and to provide better compliance than coadministration of two drugs. Compounds were synthesized using a two-step combinatorial method for C-terminal modification. In the method, the protected C-terminal-free carboxyl peptide, Boc-Tyr( tBu)- d-Ala-Gly Phe-Pro-Leu-Trp(Boc)-OH, was synthesized as a shared intermediate using Fmoc solid phase chemistry on a 2-chlorotrityl resin. This intermediate was esterified or amidated in solution phase. The structure-activity relationships (SAR) showed that the C-terminus acted as not only a critical pharmacophore for the substance P antagonist activities, but as an address region for the opioid agonist pharmacophore that is structurally distant from the C-terminal. Among the peptides, H-Tyr- d -Ala-Gly-Phe-Pro-Leu-Trp-NH-Bzl ( 3) demonstrated high binding affinities at both delta and mu receptors ( K i = 10 and 0.65 nM, respectively) with efficient agonist functional activity in the mouse isolated vas deferens (MVD) and guinea pig isolated ileum (GPI) assays (IC 50 = 50 and 13 nM, respectively). Compound 3 also showed a good antagonist activity in the GPI assay with substance P stimulation ( K e = 26 nM) and good affinity for the hNK1 receptor ( K i = 14 nM). Consequently, compound 3 is expected to be a promising and novel type of analgesic with bifunctional activities. |
| Databáze: | OpenAIRE |
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