title: Synthesis and opioid activity of N,N-dimethyl-Dmt-Tic-NH-CH(R)-R' analogues: acquisition of potent delta antagonism.
abstract: N,N-Dimethylation of the H-Dmt-Tic-NH-CH(R)-R' series of compounds produced no significant affect on the high delta-opioid receptor affinity (K(i)=0.035-0.454 nM), but dramatically decreased that for the micro-opioid receptor. The effect of N-methylation was independent of the length of the linker (R); however, the bioactivities were affected by the chemical composition of the third aromatic group (R'): phenyl (Ph) (5'-8') elicited a greater reduction in micro-affinity (40-70-fold) compared to analogues containing 1H-benzimidazole-2-yl (Bid) (9-fold). The major consequences of N,N-dimethylation on in vitro bioactivity were: (i). a loss of delta-agonism coupled with the appearance of potent delta antagonism (4'-7') (pA(2)=8.14-9.47), while 1 exhibited only a 160-fold decreased delta agonism (1') and the delta antagonism of 8 enhanced >10-fold (pA(2)=10.62, 8'); and (ii). a consistent loss of micro-affinity resulted in enhanced delta-opioid receptor selectivity. With the exception of compound 1', the change in the hydrophobic environment at the N-terminus and formation of a tertiary amine by N,N-dimethylation in analogues of the Dmt-Tic pharmacophore produced potent delta-selective antagonists.
authors.affiliation: Department of Toxicology, University of Cagliary, I-09126, Cagliary, Italy
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Balboni
authors.forename: Severo
authors.initials: S
authors.lastname: Salvadori
authors.forename: Remo
authors.initials: R
authors.lastname: Guerrini
authors.forename: Lucia
authors.initials: L
authors.lastname: Negri
authors.forename: Elisa
authors.initials: E
authors.lastname: Giannini
authors.forename: Sharon D
authors.initials: SD
authors.lastname: Bryant
authors.forename: Yunden
authors.initials: Y
authors.lastname: Jinsmaa
authors.forename: Lawrence H
authors.initials: LH
authors.lastname: Lazarus
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D007421:Intestine, Small / Q000378:metabolism; D008297:Male; D051379:Mice; D015394:Molecular Structure; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D018847:Opioid Peptides / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000037:antagonists & inhibitors*; D017450:Receptors, Opioid, mu / Q000819:agonists; D013574:Synaptosomes / Q000378:metabolism; D014649:Vas Deferens / Q000187:drug effects / Q000502:physiology
chemical_list: D009842:Oligopeptides; D018847:Opioid Peptides; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu