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

Abstract

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.

Role of 2′,6′-dimethyl-l-tyrosine (Dmt) in some opioid lead compounds

“…Again, if we consider the replacement of the benzyl group with surrogates or the introduction of substituents in the para position, its pharmacological profile further changes 23. Furthermore, the portion -Asp*-Bid can be replaced by – Asp-NH-Ph or – Asp-NH-Bzl giving δ antagonists in both cases 20. The side chain next to Bid can be altered to obtain a variety of different activities: e. g. Gly, Ala and Asp side-chains result in δ agonism; Phe side chain results in δ antagonism, and the side chains of the other more representing amino acids yield μ agonism 24.…”

Development of new methods in modern selective organic synthesis: preparation of functionalized molecules with atomic precision

“…Among these, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (TIC), being a conformationally rigid analogue of phenylalanine, attracts particular attention as an important component of highly selective enzyme inhibitors and integrin and d-opioid receptor antagonists with a broad spectrum of pharmacological activity. 136,137 The most vivid example of using the TIC pharmacophore for the drug design is the discovery of Accupril1, 138 which is currently used to treat hypertension and congestive heart failure (Fig. 5).…”

Synthesis and characterization of a novel drug-loaded polymer, poly(lactic acid-co-aminomethyl benzimidazole)

“…anticancer, antifungal, antiviral, anti-inflammatory, etc. [5][6][7][8][9][10][11][12][13]. Among them, many drug molecules have a basic skeleton of aminomethyl benzimidazole (AMB) (Figure 1).…”

“…Among them, many drug molecules have a basic skeleton of aminomethyl benzimidazole (AMB) (Figure 1). [8][9][10][11][12][13] Due to good physical properties, biocompatibility and biodegradability, polylactic acid (PLA) as an environment friendly polymer produced from renewable resource [14][15][16][17] can be used in general polymer field as packaging materials, plastic profiles, thin films, nonwovens, and clothing fibers. [18][19][20][21][22][23] Of course, for the cost reason, PLA materials are more widely used in the biomedical field as bone material, surgical sutures, eye filler, gauze dressings, drug delivery, artificial urethra, and artificial esophagus.…”