Novel C-terminus modifications of the Dmt-Tic motif: a new class of dipeptide analogues showing altered pharmacological profiles toward the opioid receptors.
The design, synthesis and pharmacological evaluation of a novel class of Dmt-Tic dipeptide analogues are described. These resulting analogues bearing different C-terminal functionalities were found to bind to the human delta receptor with high affinity. One specific class of dipeptides bearing urea/thiourea functionalities showed partial to full activation of the delta receptor. Several dipeptides also showed good binding affinities with full activation of the human kappa receptor, a novel property for those ligands.
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Departments of Chemistry and Pharmacology, AstraZeneca R&D Montreal, 7171 Frederick-Banting, Saint-Laurent, Quebec, Canada H4S 1Z9. daniel.page@astrazeneca.com
Naismith
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A
Schmidt
R
R
Coupal
M
M
Labarre
M
M
Gosselin
M
M
Bellemare
D
D
Payza
K
K
Brown
W
W
D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007546:Isoquinolines / Q000737:chemistry*; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000378:metabolism*; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000378:metabolism*; D044005:Tetrahydroisoquinolines; D014443:Tyrosine / Q000031:analogs & derivatives / Q000737:chemistry*
D004151:Dipeptides; D007546:Isoquinolines; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D044005:Tetrahydroisoquinolines; C076121:2',6'-dimethyltyrosine; C078986:1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid; D014443:Tyrosine