Further studies on lead compounds containing the opioid pharmacophore Dmt-Tic.

Some reference opioids containing the Dmt-Tic pharmacophore, especially the δ agonists H-Dmt-Tic-Gly-NH-Ph (1) and H-Dmt-Tic-NH-(S)CH(CH2−COOH)-Bid (4) (UFP-512) were evaluated for the influence of the substitution of Gly with aspartic acid, its chirality, and the importance of the −NH-Ph and N1H-Bid hydrogens in the inductions of δ agonism. The results provide the following conclusions: (i) Asp increases δ selectivity by lowering the μ affinity; (ii) −NH-Ph and N1H-Bid nitrogens methylation transforms the δ agonists into δ antagonists; (iii) the substitution of Gly with l-Asp/d-Asp in the δ agonist H-Dmt-Tic-Gly-NH-Ph gave δ antagonists; the same substitution in the δ agonist H-Dmt-Tic-NH-CH2−Bid yielded more selective agonists, H-Dmt-Tic-NH-(S)CH(CH2−COOH)-Bid and H-Dmt-Tic-NH-(R)CH(CH2−COOH)-Bid; (iv) l-Asp seems important only in functional bioactivity, not in receptor affinity; (v) H-Dmt-Tic-NH-(S)CH(CH2−COOH)-Bid(N1-Me) (10) evidenced analgesia similar to 4, which was reversed by naltrindole only in the tail flick. 4 and 10 had opposite behaviours in mice; 4 caused agitation, 10 gave sedation and convulsions.