title: Drugs interacting with G protein alpha subunits: selectivity and perspectives.
abstract: Extracellular signal molecules as diverse as hormones, neurotransmitters and photons use a signal transduction pathway involving a receptor, a G protein and effectors. Compounds that interact directly with G proteins can mimic the receptor-G protein interaction or can block the activation of G proteins by receptors. Several binding sites exist on the G alpha protein that may be exploited for the design of synthetic stimulatory or inhibitory ligands. The effector binding site is regulated by endogenous proteins and appears to be a target for selective exogenous ligands. The GTP binding site presents a large homology within the G protein families and therefore the nucleotide analogs might not be considered as a tool to discriminate between the G protein subclasses. In contrast, different experimental strategies have substantiated the specificity in the interaction between a receptor and a G protein, the receptor binding site of G proteins should be considered as potential drug targets. Drugs interfering with this site such as mastoparan and related peptides, GPAnt-2 and suramin, are lead compounds in the design of selective G protein antagonists. Benzalkonium chloride and methoctramine have agonist or antagonist properties, depending on G protein subtypes. Such compounds would be very useful to delineate the functions of G proteins and G protein-coupled receptors, to understand some side effects of drugs used in therapy and to develop new therapeutic agents.
authors.affiliation: Laboratoire de Neuroimmunopharmacologie INSERM-U425, Université de Strasbourg I, Faculté de Pharmacie bp 24, Illkirch, France.
authors.forename: A
authors.initials: A
authors.lastname: Chahdi
authors.forename: L
authors.initials: L
authors.lastname: Daeffler
authors.forename: J P
authors.initials: JP
authors.lastname: Gies
authors.forename: Y
authors.initials: Y
authors.lastname: Landry
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015926:Complement C3a / Q000737:chemistry / Q000378:metabolism; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006160:Guanosine Triphosphate / Q000378:metabolism; D006728:Hormones / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008969:Molecular Sequence Data; D009479:Neuropeptides / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000378:metabolism*; D010455:Peptides; D011073:Polyamines / Q000378:metabolism; D011955:Receptors, Drug / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014862:Wasp Venoms / Q000737:chemistry / Q000378:metabolism*
chemical_list: D006728:Hormones; D036341:Intercellular Signaling Peptides and Proteins; D009479:Neuropeptides; D018377:Neurotransmitter Agents; D010455:Peptides; D011073:Polyamines; D011955:Receptors, Drug; D014862:Wasp Venoms; C037500:mastoparan; D015926:Complement C3a; D006160:Guanosine Triphosphate; D019205:GTP-Binding Protein alpha Subunits, Gs