title: Alkyl-substituted amino acid amides and analogous di- and triamines: new non-peptide G protein activators.
abstract: Synthesis and pharmacological properties of new potent direct activators of heterotrimeric G proteins are described. Compounds were synthesized from protected amino acids with alkylamines using coupling reagents (CDI, DCC, and EDC). Alkyl-substituted amino acid amides and their corresponding di- and triamines were subjected to structure-activity analysis. All compounds activated membrane-bound HL-60 GTPases in a pertussis toxin-sensitive fashion. This suggests a specific effect of compounds on the carboxy terminus of a defined subclass of heterotrimeric G proteins, i.e., members of the G alpha i subfamily. Elongation of the alkyl chain and increasing the number of amino groups enhanced the potency of compounds on HL-60 membrane-bound GTPase. N-(2,5-Diaminopentyl)dodecylamine (21) was selected to study its mode of action employing purified pertussis toxin-sensitive G proteins. It stimulated G alpha subunits by inducing the release of bound GDP. In contrast to receptors G beta gamma complexes were not required for 21-mediated activation of G alpha. Moderate isoform selectivity of its action was observed within a group of highly homologous members of the Gi subfamily with G alpha o1 being activated at lowest concentrations, whereas higher concentrations were necessary for the stimulation of G alpha i1 or transducin. We conclude that these compounds represent important tools for studying G protein-dependent cellular functions.
authors.affiliation: Institut für Pharmazie I, Freie Universität Berlin, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Leschke
authors.forename: R
authors.initials: R
authors.lastname: Storm
authors.forename: E
authors.initials: E
authors.lastname: Breitweg-Lehmann
authors.forename: T
authors.initials: T
authors.lastname: Exner
authors.forename: B
authors.initials: B
authors.lastname: Nürnberg
authors.forename: W
authors.initials: W
authors.lastname: Schunack
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000588:Amines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D002460:Cell Line; D002462:Cell Membrane / Q000201:enzymology; D004789:Enzyme Activation; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000187:drug effects / Q000378:metabolism*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism; D018922:HL-60 Cells / Q000201:enzymology; D006801:Humans; D007202:Indicators and Reagents; D036341:Intercellular Signaling Peptides and Proteins; D046911:Macromolecular Substances; D015394:Molecular Structure; D010455:Peptides; D037342:Pertussis Toxin; D011994:Recombinant Proteins / Q000378:metabolism; D018411:Spodoptera; D013329:Structure-Activity Relationship; D014162:Transfection; D010566:Virulence Factors, Bordetella / Q000494:pharmacology; D014862:Wasp Venoms / Q000494:pharmacology
chemical_list: D000577:Amides; D000588:Amines; D007202:Indicators and Reagents; D036341:Intercellular Signaling Peptides and Proteins; D046911:Macromolecular Substances; D010455:Peptides; D011994:Recombinant Proteins; D010566:Virulence Factors, Bordetella; D014862:Wasp Venoms; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D003994:Bucladesine; C037500:mastoparan; D006160:Guanosine Triphosphate; D037342:Pertussis Toxin; D020558:GTP Phosphohydrolases; D019204:GTP-Binding Proteins