title: Side chain methyl substitution in the delta-opioid receptor antagonist TIPP has an important effect on the activity profile.
abstract: The delta-opioid antagonist H-Tyr-Tic-Phe-Phe-OH (TIPP-OH) or its C-terminal amide analogue was systematically modified topologically by substitution of each amino acid residue by all stereoisomers of the corresponding beta-methyl amino acid. The potency and selectivity (delta- vs mu- and kappa-opioid receptor) were evaluated by radioreceptor binding assays. Agonist or antagonist potency were assayed in the mouse vas deferens and in the guinea pig ileum. In the TIPP analogues containing L-beta-methyl amino acids the influence on delta-receptor affinity and on delta-antagonist potency is limited, the [(2S,3R)-beta-MePhe3]TIPP-OH analogue being among the most potent delta-antagonists reported. In the D-beta-methyl amino acid series, the [D-beta-MeTic2] analogues are delta-selective antagonists whereas [D-Tic2]TIPP-NH2 is a delta-agonist. NMR studies did not indicate any influence of the beta-methyl substituent on the conformation of the Tic residue. The [(2R,3S)-beta-MePhe3]TIPP-NH2 is a potent delta-agonist, its C-terminal carboxylic acid analogue being more delta-selective but displaying partial agonism in both the delta- and mu-bioassay. These results constitute further examples of a profound influence of beta-methyl substitution on the potency, selectivity, and signal transduction properties of a peptide.
authors.affiliation: Eenheid Organische Chemie, Vrije Universiteit Brussel, Pleinlaan 2, B-1050 Brussels, Belgium.
authors.forename: D
authors.initials: D
authors.lastname: Tourwé
authors.forename: E
authors.initials: E
authors.lastname: Mannekens
authors.forename: T N
authors.initials: TN
authors.lastname: Diem
authors.forename: P
authors.initials: P
authors.lastname: Verheyden
authors.forename: H
authors.initials: H
authors.lastname: Jaspers
authors.forename: G
authors.initials: G
authors.lastname: Tóth
authors.forename: A
authors.initials: A
authors.lastname: Péter
authors.forename: I
authors.initials: I
authors.lastname: Kertész
authors.forename: G
authors.initials: G
authors.lastname: Török
authors.forename: N N
authors.initials: NN
authors.lastname: Chung
authors.forename: P W
authors.initials: PW
authors.lastname: Schiller
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D002460:Cell Line; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D006168:Guinea Pigs; 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; D009292:Narcotic Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D016548:Prosencephalon / Q000187:drug effects / Q000378:metabolism; D011487:Protein Conformation; D011869:Radioligand Assay; D051381:Rats; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000037:antagonists & inhibitors*; D017450:Receptors, Opioid, mu / Q000819:agonists*; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines; D014649:Vas Deferens / Q000187:drug effects / Q000502:physiology
chemical_list: D009292:Narcotic Antagonists; D009842:Oligopeptides; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D044005:Tetrahydroisoquinolines; C116539:tyrosyl-1,2,3,4-tetrahydro--3-isoquinolinecarbonyl-phenylalanyl-phenylalaninamide; C082263:tyrosyl-1,2,3,4-tetrahydro-3-isoquinolinecarbonyl-phenylalanyl-phenylalanine