title: Further studies on the Dmt-Tic pharmacophore: hydrophobic substituents at the C-terminus endow delta antagonists to manifest mu agonism or mu antagonism.
abstract: Twenty N- and/or C-modified Dmt-Tic analogues yielded similar K(i) values with either [(3)H]DPDPE (delta(1) agonist) or [(3)H]N, N(Me)(2)-Dmt-Tic-OH (delta antagonist). N-Methylation enhanced delta antagonism while N-piperidine-1-yl, N-pyrrolidine-1-yl, and N-pyrrole-1-yl were detrimental. Dmt-Tic-X (X = -NHNH(2), -NHCH(3), -NH-1-adamantyl, -NH-tBu, -NH-5-tetrazolyl) had high delta affinities (K(i) = 0.16 to 1 nM) with variable mu affinities to yield nonselective or weakly mu-selective analogues. N, N-(Me)(2)Dmt-Tic-NH-1-adamantane exhibited dual delta and mu receptor affinities (K(i)delta = 0.16 nM and K(i)mu = 1.12 nM) and potent delta antagonism (pA(2) = 9.06) with mu agonism (IC(50) = 16 nM). H-Dmt-betaHTic-OH (methylene bridge between C(alpha) of Tic and carboxylate function) yielded a biostable peptide with high delta affinity (K(i) = 0.85 nM) and delta antagonism (pA(2) = 8.85) without mu bioactivity. Dmt-Tic-Ala-X (X = -NHCH(3), -OCH(3), -NH-1-adamantyl, -NHtBu) exhibited high delta affinities (K(i) = 0.06 to 0.2 nM) and elevated mu affinities (K(i) = 2.5 to 11 nM), but only H-Dmt-Tic-Ala-NH-1-adamantane and H-Dmt-Tic-Ala-NHtBu yielded delta receptor antagonism (pA(2) = 9.29 and 9.16, respectively). Thus, Dmt-Tic with hydrophobic C-terminal substituents enhanced mu affinity to provide delta antagonists with dual receptor affinities and bifunctional activity.
authors.affiliation: Department of Pharmaceutical Science and Biotechnology Center, University of Ferrara, I-441000 Ferrara, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Salvadori
authors.forename: R
authors.initials: R
authors.lastname: Guerrini
authors.forename: G
authors.initials: G
authors.lastname: Balboni
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: D000218:Adamantane / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D004151:Dipeptides / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D004558:Electric Stimulation; D020881:Enkephalin, D-Penicillamine (2,5)- / Q000378:metabolism; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D008297:Male; D008745:Methylation; D051379:Mice; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000502:physiology; D013329:Structure-Activity Relationship; D013574:Synaptosomes / Q000378:metabolism; D044005:Tetrahydroisoquinolines; D014316:Tritium; D014649:Vas Deferens / Q000187:drug effects
chemical_list: C402272:2',6'-dimethyltyrosyl-1,2,3,4-tetrahydro-3-isoquinolinecarbonyl-alanine 1-adamantane amide; D004151:Dipeptides; C402273:N,N-dimethyl-2',6'-dimethyltyrosyl-1,2,3,4-tetrahydro-3-isoquinolinecarbonyl 1-adamantane amide; D009842:Oligopeptides; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D044005:Tetrahydroisoquinolines; D014316:Tritium; D020881:Enkephalin, D-Penicillamine (2,5)-; D000218:Adamantane