Redefining the structure–activity relationships of 2,6-methano-3-benzazocines. Part 6: Opioid receptor binding properties of cyclic variants of 8-carboxamidocyclazocine

Wentland, Mark P.; Sun, Xufeng; Cohen, Dana J.; Bidlack, Jean M.

doi:10.1016/j.bmc.2008.03.066

Cited by 6 publications

(1 citation statement)

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“…Starting from the assumption that even minor chemical modifications can change the pharmacological profile of opioids, such as peptides and pseudopeptides containing the Dmt-Tic pharmacophore or nonpeptide derivatives related to morphine,33 we selected some reference compounds, especially our known δ agonists 1 and 4 , and evaluated the influence of aspartic acid and its chirality, and the importance of the –NH-Ph and N 1 H-Bid hydrogens in the induction of δ agonism. The results obtained confirmed two expectations based on prior experimental data: (i) Asp increased the δ selectivity by lowering μ affinity; and (ii) methylation of -NH-Ph and N 1 H- Bid nitrogen transformed potent δ agonists into potent δ antagonists.…”

Section: Discussionmentioning

confidence: 99%

Further Studies on Lead Compounds Containing the Opioid Pharmacophore Dmt-Tic

et al. 2008

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Opioids containing the Dmt-Tic pharmacophore, especially the δ agonists H-Dmt-Tic-Gly-NH-Ph 1 and H-Dmt-Tic-NH-(S)CH(CH 2 -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 N 1 H-Bid hydrogens relative to δ agonism. The results provide the following conclusions: (i) Asp increases δ selectivity by lowering μ affinity; (ii) -NH-Ph and N 1 H-Bid nitrogen methylation transforms δ agonists into δ antagonists; (iii) substitution of Gly with L-Asp/D-Asp in the δ agonist H-Dmt-TicGly-NH-Ph resulted in δ antagonists, while the same substitution in the δ agonist H-Dmt-Tic-NH-CH 2 -Bid yielded more selective δ agonists, H-Dmt-Tic-NH-(S)CH(CH 2 -COOH)-Bid and H-DmtTic-NH-(R)CH(CH 2 -COOH)-Bid; (iv) L-Asp seems important only for functional bioactivity, not receptor affinity; (v) H-Dmt-Tic-NH-(S)CH(CH 2 -COOH)-Bid(N 1 -Me) (10) revealed analgesia similar to 4, which was reversed by naltrindole only in the tail-flick test. Compounds 4 and 10 had opposite behaviours in mice: 4 caused agitation, while 10 gave sedation and convulsions.

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Section: Discussionmentioning

confidence: 99%