title: Potent delta-opioid receptor agonists containing the Dmt-Tic pharmacophore.
abstract: Conversion of delta-opioid receptor antagonists containing the 2',6'-dimethyl-L-tyrosine (Dmt)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic) pharmacophore into potent delta-agonists required a third heteroaromatic nucleus, such as 1H-benzimidazole-2-yl (Bid) and a linker of specified length both located C-terminally to Tic in the general formula H-Dmt-Tic-NH-CH(R)-R'. The distance between Tic and Bid is a determining factor responsible for the acquisition of delta agonism (2, 2', 3, 4, 6) or delta antagonism (8). Compounds containing a C-terminal Ala (1, 1'), Asp (5), or Asn (7) with an amide (1, 1', 5) or free acid group (7) served as delta-antagonist controls lacking the third heteroaromatic ring. A change in chirality of the spacer (2, 2') or inclusion of a negative charge via derivatives of Asp (4, 6) resulted in potent delta agonism and moderate mu agonism, although delta-receptor affinity decreased about 10-fold for 4 while mu affinity fell by over 2 orders of magnitude. Repositioning of the negative charge in the linker altered activity: H-Dmt-Tic-NH-CH(CH(2)-Bid)COOH (6) maintained high delta affinity (K(i) = 0.042 nM) and delta agonism (IC(50) = 0.015 nM), but attachment of the free acid group to Bid [H-Dmt-Tic-NH-CH(2)-Bid(CH(2)-COOH) (9)] reconstituted delta antagonism (K(e) = 0.27 nM). The data demonstrate that a linker separating the Dmt-Tic pharmacophore and Bid, regardless of the presence of a negative charge, is important in the acquisition of opioids exhibiting potent delta agonism and weak mu agonism from a parent delta antagonist.
authors.affiliation: Department of Toxicology, University of Cagliari, I-09126 Cagliari, 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: Yunden
authors.initials: Y
authors.lastname: Jinsmaa
authors.forename: Sharon D
authors.initials: SD
authors.lastname: Bryant
authors.forename: Lawrence H
authors.initials: LH
authors.lastname: Lazarus
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004558:Electric Stimulation; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007421:Intestine, Small / Q000294:innervation; D008958:Models, Molecular; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000294:innervation; D009197:Myenteric Plexus / Q000187:drug effects; D009469:Neuromuscular Junction / Q000187:drug effects / Q000502:physiology; D011869:Radioligand Assay; D051381:Rats; D017465:Receptors, Opioid, delta / Q000819:agonists* / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000378:metabolism; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines
chemical_list: C446951:2',6'-dimethyltyrosyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid; D001562:Benzimidazoles; D004151:Dipeptides; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D044005:Tetrahydroisoquinolines