Design of non-peptide agonists and antagonists at neuropeptide receptors starting from the chemical structure of neuropeptides

Non-peptide small-molecule antagonists for cholecystokinin (CCK)-A and -B receptors, tachykinin NK-1, NK-2 and NK-3 receptors and bombesin BB-1 receptors have been designed and synthesized starting from the chemical structure of the endogenous mammalian neuropeptides cholecystokinin, substance-P and bombesin, respectively. A non-peptide CCK-A agonist, with weak potency but high efficacy, was also identified from the same strategy.     

Design,synthesis and in vitro pharmacology of GluK1 and GluK3 antagonists. Studies towards the design of subtype-selective antagonists through 2-carboxyethyl-phenylalanines with substituents interacting with non-conserved residues in the GluK binding sites

In order to identify compounds selective for the GluK1 and GluK3 subtypes of kainate receptors we have designed and synthesized a series of (S)-2-amino-3-((2-carboxyethyl)phenyl)propanoic acid analogs with hydrogen bond donating and accepting substituents on the aromatic ring. Based on crystal structures of GluK1 in complex with related ligands, the compounds were designed to explore possible interactions with non-conserved residues outside the glutamate ligand binding site and challenge the water binding network. Apart from obtaining GluK1 selective antagonists one analog with a phenyl-substituted urea (compound 31) showed some preference for GluK3 over GluK1-receptors. Docking studies indicate that this preference may be attributed to contacts between the NH of the urea substituent and non-conserved Ser741 and Ser761 residues.     

Synthesis of peptide and pseudopeptide amides inhibiting the proliferation of small cell and epithelial types of lung carcinoma cells

Small cell lung cancer (SCLC) cell lines produce and secrete various peptide hormones, e.g. bombesin (BN)/gastrin releasing peptide (GRP) like peptides that are proposed to function as their autocrine growth factors. To inhibit the proliferative effect of these hormones we have synthesized short chain BN[7-14]-analogues replacing the C-terminal peptide bond by a methylene-amino (-CH₂NH-) unit and introducing d -Phe or d -Ser into position 12. As several substance P (SP) analogues were found to inhibit the growth of SCLC cells, some short chain SP-analogues have been synthesized. (Pseudo)octapeptides were synthesized in solution, by fragment condensation using the DCC/HOPfp method. Fragments and SP-analogues were synthesized stepwise using pentafluorophenyl esters. The resistance to hydrolysis of the reduced peptide bond made permitted exact quantification of the Leuψ(CH₂NH)Leu pseudopeptide in hydrolysates. The binding ability of both types of peptides to BN-receptors on Swiss 3T3 mouse fibroblast cells and their antiproliferative effect on NCI-H69 human SCLC cell line have been tested and compared with a short chain SP-antagonist pHOPA-d -Trp-Phe-d -Trp-Leu-Leu-NH₂ ( R ) previously described as a potent inhibitor of SCLC proliferation. While BN-analogues showed weak activity in inhibition of proliferation of SCLC cells, SP-analogues 6 : d -MePhe-d-T rp-Phe-d -Trp-Leuψ(CH₂NH)-Leu-NH₂ and 7 : d -MePhe-d -Trp-Phe-d -Trp-Leu-MPA, in spite of greatly diminished affinity towards the BN-receptor, inhibited SCLC proliferation more effectively than R ( 6 : IC₅₀=2 μm , 7 : IC₅₀=5 μm and R : IC₅₀=10 μm ). Moreover, 6 inhibited the respiratory activity of SK-MES 1 epithelial type of lung carcinoma cells in proliferating but not in the quiescent state, suggesting that the antiproliferative effect of these compounds is not due to simple cytotoxicity. These short chain analogues of SP might be promising candidates as therapeutic agents in the treatment of SCLC. © 1998 European Peptide Society and John Wiley & Sons, Ltd.     

Glucosensing and glucose homeostasis: from fish to mammals

This review is focused on two topics related to glucose in vertebrates. In a first section devoted to glucose homeostasis we describe how glucose levels fluctuate and are regulated in different classes of vertebrates. The detection of these fluctuations is essential for homeostasis and for other physiological processes such as regulation of food intake. The capacity of that detection is known as glucosensing, and the different mechanisms through which it occurs are known as glucosensors. Different glucosensor mechanisms have been demonstrated in different tissues and organs of rodents and humans whereas the information obtained for other vertebrates is scarce. In the second section of the review we describe the present knowledge regarding glucosensor mechanisms in different groups of vertebrates, with special emphasis in fish.