Amino acids and peptides. LII. Design and synthesis of opioid mimetics containing a pyrazinone ring and examination of their opioid receptor binding activity

• Published in: Chemical & pharmaceutical bulletin Vol. 46; no. 9; pp. 1374 - 1382
• Main Authors: Okada, Y, Tsukatani, M, Taguchi, H, Yokoi, T, Bryant, SD, Lazarus, LH
• Format: Journal Article
• Language: English
• Published: TOKYO Pharmaceutical Soc Japan 01.09.1998; Maruzen
• Subjects: Amino Acids - chemistry; Animals; Biological and medical sciences; Brain - drug effects; Brain - metabolism; Chemistry; Chemistry, Medicinal; Chemistry, Multidisciplinary; Drug Design; Life Sciences & Biomedicine; Medical sciences; Models, Molecular; Narcotics - pharmacology; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Physical Sciences; Pyrazines - chemical synthesis; Pyrazines - metabolism; Pyrazines - pharmacology; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, Opioid, delta - agonists; Receptors, Opioid, delta - metabolism; Receptors, Opioid, mu - agonists; Receptors, Opioid, mu - metabolism; Science & Technology; Structure-Activity Relationship; Synaptosomes - metabolism; Tyrosine - analogs & derivatives; Tyrosine - chemical synthesis; Tyrosine - chemistry; Tyrosine - metabolism; Tyrosine - pharmacology; RECOGNITION; OPIATE RECEPTOR; amino-containing pyrazinone derivative; CONFORMATION; ENKEPHALIN; 2(1H)-pyrazinone; POTENT; pyrazinone-containing tyrosine derivative; opioid-receptor binding activity; FACILE SYNTHESIS; DELTORPHIN; simple synthetic procedure; ANTAGONISTS; SELECTIVITY; DERIVATIVES; Aminoamide; Nitrogen heterocycle; Peptidomimetic compound; Lactam; μ Opioid receptor; Non peptide compound; δ Opioid receptor; Modeling; α-Aminoacid; Biological fixation; Structure activity relation; Molecular model; Affinity; Chemical synthesis
• ISSN: 0009-2363; 1347-5223
• DOI: 10.1248/cpb.46.1374

An amino group was introduced to the 3 or 6 position of a pyrazinone ring by cyclization of dipeptidyl chloromethyl ketones, Boc-Tyr-OH was coupled with the amino function, followed bq removal of the Boc group to give pyrazinone ring-containing tyrosine derivatives. Of the various tyrosine derivatives prepared, 5-methyl-6-beta-phenethyl-3-tyrosylaminobutyl-2(1H)-pyrazinone exhibited strong binding to the mu-opioid receptor with a K-i value of 55.8 nM and to the delta-opioid receptor with a K-i value of 2165 nM and with a K(i)mu/K(i)delta value of 0.026.