Novel Dmt-Tic dipeptide analogues as selective delta-opioid receptor antagonists.
A series of Dmt-Tic analogues with substitution on the Tic aromatic ring has been synthesized and evaluated for opioid receptor affinity and activation. Incorporation of large hydrophobic groups at position 7 of Tic did not greatly alter the delta opioid receptor binding affinities of the dipeptides whereas substitution at position 6 substantially diminished their affinity. These modified Dmt-Tic peptides showed binding affinities as low as 2.5 nM with up to 500-fold selectivity for the delta versus mu opioid receptor and proved to be delta receptor antagonists.
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Department of Chemistry, AstraZeneca R&D Montréal, Saint-Laurent, Québec, Canada. daniel.page@astrazeneca.com
McClory
A
A
Mischki
T
T
Schmidt
R
R
Butterworth
J
J
St-Onge
S
S
Labarre
M
M
Payza
K
K
Brown
W
W
D001549:Benzamides / Q000378:metabolism; D001667:Binding, Competitive; D004151:Dipeptides / Q000138:chemical synthesis* / Q000494:pharmacology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D007546:Isoquinolines / Q000737:chemistry*; D010879:Piperazines / Q000378:metabolism; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000037:antagonists & inhibitors*; D044005:Tetrahydroisoquinolines; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000737:chemistry
D001549:Benzamides; D004151:Dipeptides; D007546:Isoquinolines; D010879:Piperazines; D017465:Receptors, Opioid, delta; D044005:Tetrahydroisoquinolines; C076121:2',6'-dimethyltyrosine; C088464:4-(alpha-(4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide; C078986:1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D014443:Tyrosine