Jean Martinez

Arginine 336 and Asparagine 333 of the Human Cholecystokinin-A Receptor Binding Site Interact with the Penultimate Aspartic Acid and the C-terminal Amide of Cholecystokinin

The cholecystokinin-A receptor (CCK-AR) is a G protein-coupled receptor that mediates important central and peripheral cholecystokinin actions. Residues of the CCK-AR binding site that interact with the C-terminal part of CCK that is endowed with biological activity are still unknown. Here we report on the identification of Arg-336 and Asn-333 of CCK-AR, which interact with the Asp-8 carboxylate and the C-terminal amide of CCK-9, respectively. Identification of the two amino acids was achieved by dynamics-based docking of CCK in a refined three-dimensional model of CCK-AR using, as constraints, previous results that demonstrated that Trp-39/Gln-40 and Met-195/Arg-197 interact with the N terminus and the sulfated tyrosine of CCK, respectively. Arg-336-Asp-8 and Asn-333-amide interactions were pharmacologically assessed by mutational exchange of Arg-336 and Asn-333 in the receptor or reciprocal elimination of the partner chemical functions in CCK. This study also allowed us to demonstrate that (i) the identified interactions are crucial for stabilizing the high affinity phospholipase C-coupled state of the CCK-AR·CCK complex, (ii) Arg-336 and Asn-333 are directly involved in interactions with nonpeptide antagonists SR-27,897 and L-364,718, and (iii) Arg-336 but not Asn-333 is directly involved in the binding of the peptide antagonist JMV 179 and the peptide partial agonist JMV 180. These data will be used to obtain an integrated dynamic view of the molecular processes that link agonist binding to receptor activation.

Synthesis and in Vivo pharmacological profile of dimeric HOE 140 bradykinin antagonists

Muriel Amblard, Isabelle Daffix, Gilbert Berge, Pierre Dodey, Didier Pruneau, Jean-Luc Paquet, Pierre Belichard, Jean-Michel Luccarini and Jean Martineza Laboratoire des Aminoacides Peptides et Proteines (LAPP), ESA CNRS 5075, Universites de Montpellier I et II, Faculte de Pharmacie, 15 Av. C. Flahault, 34060 Montpellier, Cedex, France. Laboratoires de Recherche FOURNIER, Route de Dijon, 21100 Daix, France

A Novel Series of Growth Hormone Secretagogues

Growth Hormone (GH), secreted by the pituitary gland, acts directly or indirectly on the peripheral organs by stimulating the synthesis of growth factors (insulin-like growth factor-I or IGF-I). The direct action of GH is of a type referred to as anti-insulinic, which favours lipolysis at the level of adipose tissues. Through its action on IGF-I (somatomein C) synthesis and secretion, GH stimulates growth of cartilage and bones, protein synthesis and cellular proliferation in multiple peripheral organs, including muscles and skin. Through its biological activity, GH participates within adults in the maintenance of a protein anabolism state, and plays a primary role in the tissue regeneration phenomenon after a trauma.