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: Gianfranco Balboni, Severo Salvadori, Remo Guerrini, Lucia Negri, Elisa Giannini, Yunden Jinsmaa, Sharon D Bryant, Lawrence H Lazarus
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 45 Issue 25 Pg. 5556-63 (Dec 05 2002) ISSN: 0022-2623 [Print] United States
• PMID: 12459023 (Publication Type: Journal Article)

Chemical References

• 2',6'-dimethyltyrosyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid
• Benzimidazoles
• Dipeptides
• Receptors, Opioid, delta
• Receptors, Opioid, mu
• Tetrahydroisoquinolines

Topics

• Animals
• Benzimidazoles (chemical synthesis, chemistry, pharmacology)
• Binding, Competitive
• Brain (metabolism)
• Dipeptides (chemical synthesis, chemistry, pharmacology)
• Electric Stimulation
• Guinea Pigs
• In Vitro Techniques
• Intestine, Small (innervation)
• Models, Molecular
• Muscle Contraction (drug effects)
• Muscle, Smooth (drug effects, innervation)
• Myenteric Plexus (drug effects)
• Neuromuscular Junction (drug effects, physiology)
• Radioligand Assay
• Rats
• Receptors, Opioid, delta (agonists, metabolism)
• Receptors, Opioid, mu (agonists, metabolism)
• Structure-Activity Relationship
• Tetrahydroisoquinolines