title: Cationic amphiphiles with G-protein-stimulatory activity: studies on the role of the basic domain in the activation process.
abstract: 2-Substituted histamines, which are cationic-amphiphilic, activate pertussis toxin-sensitive G-proteins by a receptor-independent mechanism. Lipophilicity is an important determinant for this G-protein activation, but the influence of basicity remained unclear. We prepared four imidazole-containing compounds and nine alkylamines with different basicity and studied their effcts on high-affinity GTP hydrolysis in HL-60 membranes. The substances contained a lipophilic domain (L) and polar (P) and/or cationic (C) domains. Compared to 2-substituted histamines (L-P-C), the corresponding L-C-P type compounds were less potent and effective which, however, were still more active than L-P-P type substances. Among alkylamines, 2-octadecylaminoethyl-N,N-diethylamine (11) was the most potent GTPase activator (pEC50 = 5.7; 100% stimulation above basal). Conversely, 3-(5-hydroxyundecylamino)propylamine (15) was the most efficient compound (pEC50 = 4.3; 160% stimulation above basal). Compared to compounds 11 and 15, which belong to the L-C-C type, the corresponding L-P-C type compounds were less active. Thus, among 2-substituted histamines and alkylamines, a terminal cationic domain is critical for potent and/or effective receptor-independent G-protein activation. An L-C-X structure (X = P or C) is more favorable for G-protein activation than a L-P-X structure. Potency and efficiency of receptor-independent G-protein activators are independently determined drug parameters.
authors.affiliation: Institut für Pharmazie, Freie Universität Berlin, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Detert
authors.forename: R
authors.initials: R
authors.lastname: Seifert
authors.forename: W
authors.initials: W
authors.lastname: Schunack
mesh_terms: D000818:Animals; D001711:Biotransformation / Q000187:drug effects; D002462:Cell Membrane / Q000378:metabolism; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D020558:GTP Phosphohydrolases / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000096:biosynthesis*; D006160:Guanosine Triphosphate / Q000378:metabolism; D006168:Guinea Pigs; D018922:HL-60 Cells; D006632:Histamine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D006634:Histamine H1 Antagonists / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D016339:Spectrometry, Mass, Fast Atom Bombardment; D013055:Spectrophotometry, Infrared; D013268:Stimulation, Chemical
chemical_list: D006634:Histamine H1 Antagonists; D006632:Histamine; D006160:Guanosine Triphosphate; D020558:GTP Phosphohydrolases; D019204:GTP-Binding Proteins