Medium sized lactones with hypolipidaemic and antioxidant activity: synthesis and biological evaluation of promising dual-action anti-atherosclerosis drugs.

Macrocyclic lactones 1a-b have been synthesized and their potential therapeutic value evaluated. The key structural feature of these active 'chimera' compounds is the 12-membered lactone ring that brings together the well-known polysubstituted hydroquinone moiety of antioxidants and the alpha,alpha-dimethyl substituted acyl residue of gemfibrozil. Lactones 1a-b showed better activity than probucol, a classical phenolic antioxidant, in preventing the Cu++-induced oxidative modification of human LDL. The hypolipidaemic activity of the new lactones, evaluated as the inhibition of lipids biosynthesis in Hep-G2 cells, was comparable to that of gemfibrozil. These features, added to the lack of cytotoxicity, make this new class of medium sized lactones promising dual-action drugs useful as anti-atherosclerosis agents.

A new series of 6-chloro-2,3-dihydro-4(1H)-quinazolinone derivatives as antiemetic and gastrointestinal motility enhancing agents.

New 6-chloro-2,3-dihydro-4(1H)-quinazolinones (24-27) have been synthesized and evaluated for gastrointestinal prokinetic and antiemetic activities in comparison with structurally related benzamides (21-22) and 6-chloro-2,3-dihydro-(1H)-1,3-benzoxazolin-4-ones (28). Their key pharmacophoric element has been defined as a 6-membered ring replacing the "virtual ring" arising from the hydrogen bond between amidic nitrogen and methoxy group in metoclopramide (1) and structurally related benzamides (2-10). Variations of heterocycle linking groups have pointed out that a lipophilic aromatic group in position 1 plays an important role for pharmacological properties, while the steric restriction and the modification of the side-chain nucleophilicity are uneffective both for the in vitro and in vivo activity. Some of these compounds very effectively enhance gut peristaltic activity in vitro (rabbit jejunum), increase gastric emptying of a semisolid meal (in rats), and inhibit cisplatin-induced emesis (in pigeons), favourably comparing with cisapride.

Conformational analysis of heparin epoxide in aqueous solution. An NMR relaxation study.

1H and 13C NMR relaxation measurements at various magnetic fields have been used to characterize the nature of overall and internal motions in heparin epoxide in aqueous solution. A two-dimensional homonuclear NOESY experiment showed a considerable number of cross-relaxing protons in the molecule. The inter-proton distances calculated from NOE data were compared with those obtained by molecular mechanics calculations. Several discrepancies between the experimental and the theoretical inter-proton distances as well as the variations in 13C spin-lattice relaxation times, measured at two magnetic fields, indicated that the polysaccharide tumbles anisotropically in solution. The rates of overall and internal motions as well as the order parameters have been calculated using a model-free spectral density function. The numerical values indicate that the correlation times which characterize overall molecular motion are outside the extreme narrowing limit (tau parallel = 8 x 10(-10) s and tau perpendicular = 4.2 x 10(-8) s) and that internal motion correlation time is on a picosecond timescale.

Conformational analysis of heparin epoxide: molecular mechanics computations.

The conformation of models of the epoxy-derivative of the glycosaminoglycan heparin has been studied by molecular mechanics calculations using a MM2-like force field extended with parameters for the oxirane ring. Two dimers, two trimers and several higher homologs modeling heparin epoxide were investigated, assuming the preferred 5H0 ring form of 2,3-anhydro-alpha-L-guluronic acid residue. Two-dimensional (phi; psi) maps of dimers showed the location of the energetically preferred conformers. Starting from the most stable dimer conformers, structures of trimers and other oligomers were derived and optimized, with an exhaustive search of the preferred sidechain conformers. The effect of solvation on conformation was analyzed using a continuum model of solvent. The present calculations indicate a significant flexibility of the heparin epoxide chain.

Synthetic peptides related to the dermorphins. II. Synthesis and biological activities of new analogues.

A new series of analogues of the potent opiate-like peptides dermorphins (mainly tetra- and pentapeptides) were synthesized in order to better evaluate the structure-activity relationships. Relative potencies were referred to dermorphin (H-Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2), the prototype of this class of frog skin peptides. Peripheral opioid activity (guinea-pig ileum and mouse vas deferens) was determined for all the dermorphin analogues. For a selected number of them also central analgesic (hot plate and tail-flick tests) and cataleptic activities were assayed in the rat by intracerebroventricular administration.

Amino acid composition and sequence of dermorphin, a novel opiate-like peptide from the skin of Phyllomedusa sauvagei.

Dermorphin, a heptapeptide with very potent opiate-like activity, has been isolated from methanol extracts of the skin of the South American frog Phyllomedusa sauvagei. The amino acid sequence of the peptide is: H-Try-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2. Dermorphin presents striking differences from the known enkephalins; it offers a surprising example of a peptide from Vertebrata containing a D-amino acid residue in its sequence.

Synthesis of dermorphins, a new class of opiate-like peptides.

H-Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2 (dermorphin) and H-Tyr-D-Ala-Phe-Gly-Tyr-Hyp-Ser-NH2 (Hyp6-dermorphin) are two members of a new class of opiate-like peptides present in the amphibian skin. Their syntheses and that of the L-Ala2-analogue of dermorphin have been accomplished by conventional segment condensation in solution.

Synthetic peptides related to the dermorphins. I. Synthesis and biological activities of the shorter homologues and of analogues of the heptapeptides.

Dermorphins are potent opiate-like peptides isolated from the skin of some species of frogs. They are characterized by the presence of a D-amino acid residue, which is crucial for bioactivity. A number of analogues were prepared in order to evaluate the structure-activity relationships. The syntheses were accomplished either by conventional or solid-phase procedures. In vitro assays included both guinea pig ileum (GPI) and mouse vas deferens (MVD) preparations. Central analgesic (tail-flick and hot plate tests) and cataleptic activities were determined in the rat by intracerebroventricular route. The potency of dermorphin (H- Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2) in the different tests was: GPI: IC50 = 3.3 nM; MVD: IC50 = 29 nM; hot plate: ED50 = 13.3 pmol/rat; tail-flick: ED50 = 23 pmol/rat; catalepsy: ED50 = 130 pmol/rat.