title: Evolution of the Dmt-Tic pharmacophore: N-terminal methylated derivatives with extraordinary delta opioid antagonist activity.
abstract: The delta opioid antagonist H-Dmt-Tic-OH (2',6'-dimethyl-L-tyrosyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) exhibits extraordinary delta receptor binding characteristics [Ki delta = 0.022 nM; Ki mu/Ki delta = 150,000] and delta antagonism (pA2 = 8.2; Ke = 5.7 nM). A change in chirality of Dmt at C alpha (1, 2, 6, 8, 10, 13) curtailed delta receptor parameters, while replacement of its alpha-amino function by a methyl group (3) led to inactivity; Tyr-Tic analogues 4 and 11 weakly interacted with delta receptors. N-Alkylation of H-Dmt-Tic-OH and H-Dmt-Tic-Ala-OH with methyl groups produced potent delta-opioid ligands with high delta receptor binding capabilities and enhanced delta antagonism: (i) N-Me-Dmt-Tic-OH 5 had high delta opioid binding (Ki delta = 0.2 nM), elevated delta antagonism on mouse vas deferens (MVD) (pA2 = 8.5; Ke = 2.8 nM), and nondetectable mu activity with guinea pig ileum (GPI). (ii) N,N-Me2-Dmt-Tic-OH (12) was equally efficacious in delta receptor binding (Ki delta = 0.12 nM; Ki mu/Ki delta = 20000), but delta antagonism rose considerably (pA2 = 9.4; Ke = 0.28 nM) with weak mu antagonism (pA2 = 5.8; Ke = 1.58 microM; GPI/MVD = 1:5640). N-Me-(9) and N,N-Me2-Dmt-Tic-Ala-OH (15) also augmented delta opioid receptor binding, such that 15 demonstrated high affinity (Ki delta = 0.0755 nM) and selectivity (Ki mu/Ki delta = 20132) with exceptional antagonist activity on MVD (pA2 = 9.6; Ke = 0.22 nM) and weak antagonism on GPI (pA2 = 5.8; Ke = 1.58 microM; GPI/MVD = 1:7180). Although the amidated dimethylated dipeptide analogue 14 had high Ki delta (0.31 nM) and excellent antagonist activity (pA2 = 9.9; Ke = 0.12 nM), the increased activity toward mu receptors in the absence of a free acid function at the C-terminus revealed modest delta selectivity (Ki mu/Ki delta = 1655) and somewhat comparable bioactivity (GPI/MVD = 4500). Thus, the data demonstrate that N,N-(Me)2-Dmt-Tic-OH (12) and N,N-Me2-Dmt-Tic-Ala-OH (15) retained high delta receptor affinities and delta selectivities and acquired enhanced potency in pharmacological bioassays on MVD greater than that of other peptide or non-peptide delta antagonists.
authors.affiliation: Department of Pharmaceutical Science, University of Ferrara, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Salvadori
authors.forename: G
authors.initials: G
authors.lastname: Balboni
authors.forename: R
authors.initials: R
authors.lastname: Guerrini
authors.forename: R
authors.initials: R
authors.lastname: Tomatis
authors.forename: C
authors.initials: C
authors.lastname: Bianchi
authors.forename: S D
authors.initials: SD
authors.lastname: Bryant
authors.forename: P S
authors.initials: PS
authors.lastname: Cooper
authors.forename: L H
authors.initials: LH
authors.lastname: Lazarus
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D002462:Cell Membrane / Q000378:metabolism; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D020881:Enkephalin, D-Penicillamine (2,5)-; D004745:Enkephalins / Q000378:metabolism; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D008745:Methylation; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D009292:Narcotic Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000502:physiology; D017450:Receptors, Opioid, mu / Q000187:drug effects / Q000502:physiology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014649:Vas Deferens / Q000187:drug effects / Q000502:physiology
chemical_list: D004151:Dipeptides; D004745:Enkephalins; D007202:Indicators and Reagents; D007546:Isoquinolines; D009292:Narcotic Antagonists; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D020881:Enkephalin, D-Penicillamine (2,5)-