Morphine conformation-dependent lipophilicity

Gaillard, P. Carrupt, P.-A. Testa, B., The conformation-dependent lipophilicity of morphine glucuronides as calculated from the molecular lipophilicity potential, Bioorg. Med. Chem. Lett. 4, 737-742 (1994). 

Gaillard, R, Carrupt, P.-A. and Testa, B. (1994a). The Conformation-Dependent Lipophilicity of Morphine Glucuronides as Calculated from their Molecular Lipophilicity Potential. Bioorg. Med.Chem.Lett., 4,737-742. 

Carrupt PA, Testa B, Bechalany A, El Tayar N, Descas P and Perrissoud D, Morphine-6-glucuronide and morphine-3-glucuronide as molecular chameleons with unexpected lipophilicity, /. Med. Chem., 34, 1272-1275 (1991). NB See Walther B, Carrupt PA, El Tayar N and Testa B, 8-Substituted xanthines as phosphodiesterase inhibitors Conformation-dependent lipophilicity and structure-activity relationships, Helv. Chim. Acta, 72,507-517 (1989). 

Calculations reported by Gaillard et al. [145] show that the lipophilicity of morphine glucuronides is conformation-dependent. These compounds exist as folded and extended conformers that differ in their partition behavior. They are hydrophilic in water and less polar in lipid environments such as membranes. 

The three prototype mixed p agonist/S antagonists described in this chapter have excellent potential as analgesics with low propensity to produce tolerance and dependence. The pseudotetrapeptide DIPP-NH2[ ] has already been shown to produce a potent analgesic effect, less tolerance than morphine, and no physical dependence upon chronic administration. In preliminary experiments, the tetrapeptides DIPP-NH2 and DIPP-NH2[T] were shown to cross the BBB to some extent, but further structural modifications need to be performed in order to improve the BBB penetration of these compounds. The Tyr-Tic dipeptide derivatives can also be expected to penetrate into the central nervous system because they are relatively small, lipophilic molecules. In this context, it is of interest to point out that the structurally related dipeptide H-Dmt-D-Ala-NH-(CH2)3-Ph (SC-39566), a plain p-opioid agonist, produced antinociception in the rat by subcutaneous and oral administration [72], As indicated by the results of the NMR and molecular mechanics studies, the conformation of the cyclic p-casomorphin analogue H-Tyr-c[-D-Orn-2-Nal-D-Pro-Gly-] is stabilized by intramolecular hydrogen bonds. There-... 

---

See also in sourсe #XX -- [ ]

---