Beta-casomorphin (5) Tyr-Pro-Phe-Pro-Gly, a partial sequence of bovine beta-casein with moderate opioid properties and mu-receptor affinity, was modified by substituting for the natural L-amino acids their D-analogs, and D-pipecolic acid, as well as by amidation of the C-terminal. Substitution of D-Pro or D-pipecolic acid for L-Pro4 considerably increased the analgesic action and the potency on guinea-pig ileum of beta-casomorphin (5) as well as of casomorphin [4] amide. The resulting D-Pro4 analogs Deprolorphin and Deproceptin which showed high analgesic potency after both intracerebroventricular and intravenous administrations. Also, the substitution of D-Phe for L-Phe3 enhanced, even though to a lesser degree, the antinociceptive action. Both naltrexone and naloxone completely blocked the effects in vivo and in vitro. The substitution of D-Pro for L-Pro2 abolished the opioid-like actions, while substituting D-pipecolic acid for L-Pro2 resulted in an increased analgesic effect of remarkably long duration. The correlation of analgesic action with the effects on isolated organs separates the L-Pro4-substituted derivatives and D-Phe3-CM(5) from the other modified casomorphins and morphine, indicating that the analgesic potency of the former was about ten times that of the latter group in the case of identical GPI-potency. This may involve different subpopulations of opiate mu-receptors.

Amino Acid Sequence↗

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Opiate receptor binding affinities of some D-amino acid substituted beta-casomorphin analogs.

beta-Casomorphin-(5) and some analogs modified by the introduction of some D-amino acids and D-pipecolic acid as well as by C-terminal amidation were tested for their affinities to mu- and delta-binding sites in rat brain membranes. The binding affinities of these compounds are compared with the known activities in the guinea pig ileum (GPI) and mouse vas deferens (MVD) test and their antinociceptive potencies in rats. The substitution of D-proline for proline in position 4 in beta-casomorphin-(5) and beta-casomorphin-(4)amide (morphiceptin) results in derivatives with very high mu-binding affinity and mu-selectivity. These affinities correspond to the respective analgesic potencies. Both binding to mu-receptors and analgesic potency are also enhanced by the introduction of D-Phe in position 3. Testing D-Ala2 substituted derivatives with respect to their ability to compete for 3H-naloxone, we observed apparent differences between the pentapeptide amides (biphasic displacement curves) and the tetrapeptide amides (monophasic displacement curves). The substitution of L-Pro2 by D-pipecolic acid yields an analog with preferential delta-receptor affinity in the organ preparations (MVD) but preferential mu-receptor affinity in brain membranes. This finding suggests a possible difference between peripheral and central mu-binding sites.

Amino Acids↗

PubMedDate not supplied

Nonopioid effects of beta-casomorphin-5 in guinea pig heart: alterations to the beta-adrenoceptor-G-protein complex and inhibition of myocardial responses to isoproterenol.

The influence of beta-casomorphin-5 on the beta-adrenoceptor complex in guinea pig heart membranes was studied by means of binding studies, G-protein investigations and isolated heart preparations. In nanomolar concentrations beta-CM-5 induced an increase in receptor affinity towards the agonist isoproterenol whereas the antagonist affinity was reduced. The isoproterenol-stimulated increase in cardiac contractility, moreover, is reduced by 10 nM beta-CM-5. Furthermore, beta-CM-5 was found to inhibit the isoproterenol-induced GDP/GTP exchange as well as the [35S]GTP[S] binding to guinea pig heart membranes, indicating an involvement of G-proteins. These findings suggest that low concentrations of beta-CM-5 modulate the functional properties of the myocardial beta-adrenoceptor-G-protein complex, presumably resulting in its desensitization. The observed effects of beta-CM-5 are not prevented by naloxone and, therefore, are nonopioid in nature.

Amino Acid Sequence↗

PubMedDate not supplied

Structure-activity relationships of cyclic beta-casomorphin-5 analogues.

Cyclic analogues of the beta-casein-derived opioid peptide beta-casomorphin-5 (H-Tyr-Pro-Phe-Pro-Gly-OH) were prepared through substitution of the Pro2 residue with various alpha,omega-diamino acid residues (lysine, ornithine, 2,4-diaminobutyric acid) and cyclization of the omega-amino group to the C-terminal carboxyl function. Compounds of this type, with D-configuration at the 2-position residue, showed high opioid receptor affinity with some preference for mu receptors over delta receptors, high potency in the guinea pig ileum assay and considerable activity in the mouse vas deferens assay. Configurational inversion at the 4-position in these cyclic analogues resulted in enhanced affinity for both mu and delta receptors, whereas N-methylation of the Phe3 residue produced a potency decrease.

Amino Acid Sequence↗

PubMedDate not supplied

CT and MRI in acute hemorrhagic stroke.

We report the case of a woman presenting with an acute onset of hemiplegia. MRI was performed and showed a hyperintense mass on diffusion-weighted imaging, with areas of high signal intensity on T2* imaging and T2/PD imaging. T1-weighted imaging showed a more inhomogeneous lesion with a central isointense part corresponding to the acute clot, as well as a peripheral crescent of hypointense plasma; since another mass lesion could not be acutely excluded, computed tomography was performed immediately afterwards, showing a hyperdense hematoma. The patient was taken to the neurosurgical operating theater, where she underwent decompressive craniotomy and evacuation of the hematoma.

Acute Disease↗

PubMedDate not supplied

Vaccine therapy for malignant melanoma.

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Combined Modality Therapy↗