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Assessment of substitution in the second pharmacophore of Dmt-Tic analogues |
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| Authors: | Santagada V Balboni G Caliendo G Guerrini R Salvadori S Bianchi C Bryant S D Lazarus L H |
| Affiliation: | a Medicinal Chemistry and Toxicology, University of Naples, I-80134 Naples, Italy b Department of Toxicology, University of Cagliari, I-09126 Cagliari, Italy c Department of Pharmaceutical Sciences and Biotechnology Center, University of Ferrara, I-4100 Ferrara, Italy d Institute of Pharmacology, University of Ferrara, I-44100 Ferrara, Italy e Peptide Neurochemistry, LCBRA, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27707, USA |
| Abstract: | The Dmt-Tic pharmacophore exhibits potent δ-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 δ affinity (1′, 2, 7, and 9), but exhibited low to non-selectivity toward μ receptors similar to H-Dmt-Tic-amide and H-Dmt-Tic-ol. Functional bioactivity indicated high δ antagonism (pA2 7.4–7.9) (1′, 2, and 9) and modest μ agonism, pEC50 (6.1–6.3) (1′, 2, 8, and 9), but with Emax values analogous to dermorphin. These Dmt-Tic analogues with mixed δ antagonist/μ agonist properties would appear to be better candidates as analgesics than pure μ agonists. |
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