Evolution of the Bifunctional Lead μ Agonist/δ Antagonist Containing the 2′,6′-Dimethyl-l-tyrosine−1,2,3,4-Tetrahydroisoquinoline-3-carboxylic Acid (Dmt−Tic) Opioid Pharmacophore

Recently, bifunctional opioids characterized by a μ agonist/δ antagonist pharmacological profile are gaining renewed importance as potential drugs for the treatment of pain on the basis of their low propensity to induce tolerance and physical dependence (1−3). Furthermore, a project involving the use of our lead μ agonist/δ antagonist H-Dmt-Tic-Gly-NH-Bzl (4), (coded UFP-505) in the treatment of pain resulting from cancer was funded by the University of Leicester (UK) [https://swww2.le. ac.uk/ebulletin/news/press-releases/2000-2009/2008/12/nparticle.2008-12-05.9756874495]. In the 1990s, a series of articles demonstrated the potential utility of bifunctional ligands in pain relief with lower central or peripheral side effects (5−14). Although the majority of opioids act directly on the central nervous system to relieve pain, their activities on peripheral tissues are responsible for many of the secondary complications associated with the management of pain. A recently recognized peripheral effect of opioids and their receptors is the promotion of angiogenesis-dependent tumor growth (15). Opioids at physiologically relevant concentrations promote angiogenesis in vitro, as well as in breast cancer and in wound healing in rodents (16−18). Although naloxone and naltrexone can inhibit tumor growth in rodents (16,19,20), nonselective opioid antagonists cannot be used to counteract the unwanted effects of opioids without also compromising analgesia in a clinical setting. Therefore, it is important to identify agents that maintain the analgesic effect of opioids while inhibiting their angiogenic effect. This goal could be reached, for example, through the coadministration of morphine and the δ selective antagonist naltrindole, instead of the nonselective antagonists naloxone or naltrexone. Considering that bifunctional ligands may have advantages compared with drug combinations, such as more predictable pharmacokinetic and pharmacodynamic relationship as a consequence of the administration of a single drug (1), we focused our attention on the lead μ agonist/δ antagonist H-Dmt-Tic-Gly-NH-Bzl (4) as a potential analgesic displaying a lower induction of tolerance, a lower physical dependence, and a lower angiogenetic propensity compared with morphine. In previous studies regarding the Dmt−Tic opioid pharmacophore, it was demonstrated that the importance of the C-terminal group in the induction of different pharmacological profiles were as follows: -NH-Ph, μ agonist/δ agonist (4); -NH-Bzl, μ agonist/δ antagonist (4); and -NH-CH2-Bid (4), -NH-CH(CH3)-Bid (21), -NH-CH(CH2-COOH))-Bid (21), δ agonists. On the basis of the new interest in opioid bifunctional μ agonist/δ antagonist ligands, it would be valuable to increase the number of compounds endowed with such a profile for more thorough pharmacological investigations in the future. As a result, H-Dmt-Tic-Gly-NH-Bzl (1) was selected as a starting point for the synthesis of some new analogues modified on the C-terminal benzyl group. A minireview by Schiller et al. (22) prompted us to evaluate the electronic and steric hindrance effects by inserting electron-donating or -withdrawing groups in the para position of the phenyl ring (3−6) and by the employment of benzyl surrogates (7, 8). Finally, although the Tyr/Dmt-d-Tic pharmacophore is considered to contain the wrong stereochemistry (23−25), our curiosity encouraged us to synthesize the diastereomer of the lead compound (1), which resulted in the formation of H-Dmt-d-Tic-Gly-NH-Bzl (2).