J. M. García Antón

New glycosylpeptides with high antinociceptive activity.

The antinociceptive activity of two new synthetic glucoside and galactoside enkephalinamide analogues was studied. The effects produced by the new analogues were compared with those obtained with [D-Met2,Hyp5]enkephalinamide and with morphine. The analogues were injected into the fourth ventricle and intrathecally. Tail immersion and paw pressure behavioural tests were used to assess antinociception. One of the analogues studied, O1,5-[beta-D-galactopyranosyl] [D-Met2,Hyp5]enkephalinamide appears to be 57,000 times more potent than morphine.

Interaction energies of mixing phosphatidylserine and phosphatidylcholine monolayers

Abstract The interactions between phosphatidylcholine and phosphatidylserine spread in monolayers of different molecular composition were studied. The influence in these mixtures of Na + and Ca 2+ ions was also determined. By applying the Goodrich, and Pagano and Gershfeld equations, the mixing energies and interactions at intermediate and collapse pressures were calculated. The maximum interaction occurs at higher pressures and in the presence of Ca 2+ ions.

Kinetically controlled enzyme-catalyzed synthesis of kyotorphin. An optimization study.

Regarding the α-chymotrypsin-catalyzed synthesis of Z-TyrArg-NH2, the effect on the reaction yield of the following experimental factors is discussed: DMF/buffer proportions, reaction temperature, and donor/nucleophile ratios. The experimental design shows that relatively better yields are obtained by increasing the reaction temperature and lowering the cosolvent proportion while maintaining a slight excess of nucleophile. The ascensional line reaches an optimal response surface very flat voided of a well-defined maximum.

Antinociceptive activity of glycosidic enkephalin analogues.

The antinociceptive activity of two new enkephalin analogues:N1.5-(β-d-glucopyranosyl)[d-Met2, Pro5]enkephalinamide andN1.5-(β-d-galactopyranosyl)[d-Met2, Pro5]enkephalinamide was assessed using the tail immersion and paw pressure behavioural tests. Both enkephalin analogues appear to be more active than morphine when injected either into the fourth ventricle or intrathecally; the galactose analogue is more than 5000 times more active than morphine when injected into the fourth ventricle. The analgesic effects produced by the analogues are partially reversed by SC naloxone (0.1 mg/kg) and totally reversed when the dose of naloxone used was 1 mg/kg, suggesting that the analogues act upon more than one type of opiate receptor (μ/δ).

Interaction of analgesics with lecithin and ganglioside monolayers

Abstract Using monolayers as a membrane model, the interaction of dextrometorphan, codeine and phentanyle with lecithin and ganglioside was studied. The penetration kinetics of these drugs into the monolayers were measured at 5 and 20 mN · m−1 and the results show that the interaction of phentanyl is maximal with lecithin, but not with ganglioside. This fact seems to exclude GM1 as a μ-opioid receptor.

Physicochemical interaction of opioid peptides with phospholipids and membranes

The surface activity and opioid potency of peptide analogues of enkephalins are described. The molecules under study have as a general formula: Tyr-D · Met-Gly-Phe-Pro-NH-(CH2)n-CH3, n being 5, 9 or 13. The interaction of these peptide-alkylamides with PC, PS, PI and GM1 monolayers and their opioid activity measured by the GPI (guinea pig ileum) test are highly dependent on the hydrophobicity of the molecule. Moreover, the GPI muscle contraction records show a strong hydrophobic interaction between the peptides and the bilayer components, that holds the molecules anchored to the membrane and increases the duration of the effect.

Preparation and in vitro activity of liposome encapsulated opioids

Four opiate molecules: morphine, naloxone, meperidine and codeine have been encapsulated in liposomes. The encapsulation efficiency has been studied as a function of the following parameters: liposome preparation method, lipid composition and opioid molecule hydrophobicity. The most important parameter as far as the entrapment efficiency is concerned is the liposome preparation method. The opioid activity of these molecules in vitro (Guinea Pig Ileum preparation) has been determined. No differences in the IC50 values could be found between encapsulated and free drug molecules.

LIPOENKEPHALINS: A STUDY OF THE SURFACE ACTIVE AND PHARMACOLOGICAL PROPERTIES OF THESE NEW MORPHINE-LIKE PEPTIDES∗

ABSTRACT By modifying the physicochemical character of naturally occurring enkephalines, a parallelism between physicochemical behavior and pharmacological activity has been found. This was achieved by introducing alkyl residues of different chain length in position 1 or 5 on the enkephalin sequence. These kinds of substances can be referred to as 1ipoenkephalins and from a physicochemical point of view can be considered as surface active agents. On the other hand, as biological activity is greatly dependent on the conformation or orientation adopted by the molecule, we have also tried to investigate possible conformational or orientation changes when increasing the hydrophobic residue by means of optical rotation measurements and compression isotherm determinations. Finally, as the enkephalin molecule itself suffers an extremely rapid inactivation in brain tissues due to the proteolitic enzyme action, several tests to check the resistance of lipoenkephalins to en zymatic hydrolysis have been carried out,...

Mixed monolayers composed of PC/PS/Chol. Interaction with opioid molecules

The miscibility of phosphatidylserine, phosphatidylcholine, and cholesterol in monolayers were studied. The influence of sodium and calcium ions in this system was determined. The compression isotherms of mixed monolayers of the above cited three components spread on subphases containing opiate molecules are elucidated. Moreover, the penetration kinetics of opiate molecules in these mixed monolayers was also recorded. The results show that the presence of cholesterol always lowers the penetration of opioid molecules; this effect is weaken for meperidine, the most hydrophobic of the molecules assayed.

Interaction of opioid molecules with PS, PC and PS/PC monolayers

The interaction between opiate molecules and phosphatidylserine (PS) or phosphatidylcholine (PC) has been studied on compression isotherms and penetration kinetics. Phosphatidylcholine-opiate interactions are weak and similar in magnitude for all opiate molecules. On contrary, PS and PS/PC interact strongly and differently with opiate molecules. The differences in penetration are not directly related to the pKa or hydrophobicity of the molecules.