title: Inverse agonism by Dmt-Tic analogues and HS 378, a naltrindole analogue.
abstract: The potent delta-opioid receptor antagonist H-2',6-L-tyrosine(Dmt)-1, 2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic-OH) exhibited partial inverse agonism (EC(50)=6.35 nM, E(max)=-18.87%) for [35S]GTPgammaS binding and H-Dmt-Tic-NH(2) was a neutral antagonist (no effect up to 30 microM). In contrast N,N(CH(3))(2)-Dmt-Tic-NH(2) was a full inverse agonist (EC(50)=2.66 nM, E(max)=-35.95%) similar to ICI 174864 ([N,N-diallyl-Tyr(1),Aib(2,3),Leu(5)]enkephaline) but with a 3.5-fold higher EC(50). In comparison, naltrindole was a neutral antagonist while its analogue HS 378 was a partial inverse agonist (E(max)=-12.99%).
authors.affiliation: Department of Pharmacology, AstraZeneca R&D Montreal, Quebec, H4S 1Z9, St-Laurent, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Labarre
authors.forename: J
authors.initials: J
authors.lastname: Butterworth
authors.forename: S
authors.initials: S
authors.lastname: St-Onge
authors.forename: K
authors.initials: K
authors.lastname: Payza
authors.forename: H
authors.initials: H
authors.lastname: Schmidhammer
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: S D
authors.initials: SD
authors.lastname: Bryant
authors.forename: L H
authors.initials: LH
authors.lastname: Lazarus
mesh_terms: D001549:Benzamides / Q000494:pharmacology; D044482:Benzeneacetamides; D001667:Binding, Competitive / Q000187:drug effects; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004151:Dipeptides / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D007546:Isoquinolines / Q000737:chemistry / Q000494:pharmacology*; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D017465:Receptors, Opioid, delta / Q000819:agonists* / Q000037:antagonists & inhibitors; D017473:Receptors, Opioid, kappa / Q000819:agonists; D017450:Receptors, Opioid, mu / Q000819:agonists; D013462:Sulfur Radioisotopes; D044005:Tetrahydroisoquinolines
chemical_list: D001549:Benzamides; D044482:Benzeneacetamides; D004151:Dipeptides; D007546:Isoquinolines; D009292:Narcotic Antagonists; D010879:Piperazines; D011759:Pyrrolidines; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D013462:Sulfur Radioisotopes; D044005:Tetrahydroisoquinolines; C100957:tyrosyl-1,2,3,4-tetrahydro-3--isoquinoline-carbonyl-alanine; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; C088464:4-(alpha-(4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D009271:Naltrexone; C055382:naltrindole; C045444:U 69593