Abstract
The Dmt-Tic pharmacophore exhibits potent delta-opioid receptor antagonism. Analogues with substitutions in the second pharmacophore with (1, 1') or without a COOH function (2-9) were synthesized: several had high delta affinity (1', 2, 7, and 9), but exhibited low to non-selectivity toward mu receptors similar to H-Dmt-Tic-amide and H-Dmt-Tic-ol. Functional bioactivity indicated high delta antagonism (pA2 7.4-7.9) (1', 2, and 9) and modest mu agonism, pEC50 (6.1-6.3) (1', 2, 8, and 9), but with Emax values analogous to dermorphin. These Dmt-Tic analogues with mixed delta antagonist/mu agonist properties would appear to be better candidates as analgesics than pure mu agonists.
MeSH terms
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Analgesics / chemical synthesis*
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Analgesics / metabolism
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Animals
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Binding, Competitive
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Dipeptides / chemical synthesis
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Dipeptides / pharmacology*
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Guinea Pigs
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Inhibitory Concentration 50
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Isoquinolines / chemical synthesis
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Isoquinolines / metabolism*
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Mice
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Receptors, Opioid, mu / agonists
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Receptors, Opioid, mu / antagonists & inhibitors
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Receptors, Opioid, mu / metabolism
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Structure-Activity Relationship
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Tetrahydroisoquinolines*
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Tyrosine / analogs & derivatives*
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Tyrosine / chemical synthesis
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Tyrosine / metabolism*
Substances
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Analgesics
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Dipeptides
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Isoquinolines
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Receptors, Opioid, mu
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Tetrahydroisoquinolines
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2',6'-dimethyltyrosine
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1,2,3,4-tetrahydroisoquinoline carboxylic acid
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Tyrosine