title: Novel Dmt-Tic dipeptide analogues as selective delta-opioid receptor antagonists.
abstract: A series of Dmt-Tic analogues with substitution on the Tic aromatic ring has been synthesized and evaluated for opioid receptor affinity and activation. Incorporation of large hydrophobic groups at position 7 of Tic did not greatly alter the delta opioid receptor binding affinities of the dipeptides whereas substitution at position 6 substantially diminished their affinity. These modified Dmt-Tic peptides showed binding affinities as low as 2.5 nM with up to 500-fold selectivity for the delta versus mu opioid receptor and proved to be delta receptor antagonists.
authors.affiliation: Department of Chemistry, AstraZeneca R&D Montréal, Saint-Laurent, Québec, Canada. daniel.page@astrazeneca.com
authors.forename: D
authors.initials: D
authors.lastname: Pagé
authors.forename: A
authors.initials: A
authors.lastname: McClory
authors.forename: T
authors.initials: T
authors.lastname: Mischki
authors.forename: R
authors.initials: R
authors.lastname: Schmidt
authors.forename: J
authors.initials: J
authors.lastname: Butterworth
authors.forename: S
authors.initials: S
authors.lastname: St-Onge
authors.forename: M
authors.initials: M
authors.lastname: Labarre
authors.forename: K
authors.initials: K
authors.lastname: Payza
authors.forename: W
authors.initials: W
authors.lastname: Brown
mesh_terms: D001549:Benzamides / Q000378:metabolism; D001667:Binding, Competitive; D004151:Dipeptides / Q000138:chemical synthesis* / Q000494:pharmacology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D007546:Isoquinolines / Q000737:chemistry*; D010879:Piperazines / Q000378:metabolism; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000037:antagonists & inhibitors*; D044005:Tetrahydroisoquinolines; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000737:chemistry
chemical_list: D001549:Benzamides; D004151:Dipeptides; D007546:Isoquinolines; D010879:Piperazines; D017465:Receptors, Opioid, delta; D044005:Tetrahydroisoquinolines; C076121:2',6'-dimethyltyrosine; C088464:4-(alpha-(4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide; C078986:1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D014443:Tyrosine