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Identification of allosteric antagonists of receptor-guanine nucleotide-binding protein interactions. 1990

R R Huang, and R N Dehaven, and A H Cheung, and R E Diehl, and R A Dixon, and C D Strader
Department of Molecular Pharmacology and Biochemistry, Merck, Sharp, and Dohme Research Laboratories, Rahway, New Jersey 07065.

A series of compounds that inhibit the coupling of the alpha 2-adrenergic receptor and the beta 2-adrenergic receptor to the guanine nucleotide-binding proteins (G proteins) Gi and Gs, respectively, have been identified. This inhibition of G protein coupling was detected by the ability of the compounds to reduce the affinity of these receptors for agonists without affecting antagonist affinity. Analysis of the structure-activity relationships of these compounds revealed a requirement for regularly spaced anionic substituents on amphipathic structures for this inhibition to occur. The compounds do not interact at the ligand binding site of the receptor or at the GTP binding site of the G protein. The identification of compounds that can uncouple receptors from G proteins demonstrates the potential for the discovery of small molecule inhibitors of receptor-G protein interactions that act as allosteric antagonists at this site.

UI MeSH Term Description Entries
D009282 Naphthalenesulfonates A class of organic compounds that contains a naphthalene moiety linked to a sulfonic acid salt or ester.
D011485 Protein Binding The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific protein-binding measures are often used as assays in diagnostic assessments. Plasma Protein Binding Capacity,Binding, Protein
D011942 Receptors, Adrenergic, alpha One of the two major pharmacological subdivisions of adrenergic receptors that were originally defined by the relative potencies of various adrenergic compounds. The alpha receptors were initially described as excitatory receptors that post-junctionally stimulate SMOOTH MUSCLE contraction. However, further analysis has revealed a more complex picture involving several alpha receptor subtypes and their involvement in feedback regulation. Adrenergic alpha-Receptor,Adrenergic alpha-Receptors,Receptors, alpha-Adrenergic,alpha-Adrenergic Receptor,alpha-Adrenergic Receptors,Receptor, Adrenergic, alpha,Adrenergic alpha Receptor,Adrenergic alpha Receptors,Receptor, alpha-Adrenergic,Receptors, alpha Adrenergic,alpha Adrenergic Receptor,alpha Adrenergic Receptors,alpha-Receptor, Adrenergic,alpha-Receptors, Adrenergic
D011943 Receptors, Adrenergic, beta One of two major pharmacologically defined classes of adrenergic receptors. The beta adrenergic receptors play an important role in regulating CARDIAC MUSCLE contraction, SMOOTH MUSCLE relaxation, and GLYCOGENOLYSIS. Adrenergic beta-Receptor,Adrenergic beta-Receptors,Receptors, beta-Adrenergic,beta Adrenergic Receptor,beta-Adrenergic Receptor,beta-Adrenergic Receptors,Receptor, Adrenergic, beta,Adrenergic Receptor, beta,Adrenergic beta Receptor,Adrenergic beta Receptors,Receptor, beta Adrenergic,Receptor, beta-Adrenergic,Receptors, beta Adrenergic,beta Adrenergic Receptors,beta-Receptor, Adrenergic,beta-Receptors, Adrenergic
D002460 Cell Line Established cell cultures that have the potential to propagate indefinitely. Cell Lines,Line, Cell,Lines, Cell
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000494 Allosteric Regulation The modification of the reactivity of ENZYMES by the binding of effectors to sites (ALLOSTERIC SITES) on the enzymes other than the substrate BINDING SITES. Regulation, Allosteric,Allosteric Regulations,Regulations, Allosteric
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D013329 Structure-Activity Relationship The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships
D013565 Sympatholytics Drugs that inhibit the actions of the sympathetic nervous system by any mechanism. The most common of these are the ADRENERGIC ANTAGONISTS and drugs that deplete norepinephrine or reduce the release of transmitters from adrenergic postganglionic terminals (see ADRENERGIC AGENTS). Drugs that act in the central nervous system to reduce sympathetic activity (e.g., centrally acting alpha-2 adrenergic agonists, see ADRENERGIC ALPHA-AGONISTS) are included here. Sympathetic-Blocking Agents,Sympatholytic,Sympatholytic Agent,Sympatholytic Drug,Sympatholytic Agents,Sympatholytic Drugs,Sympatholytic Effect,Sympatholytic Effects,Agent, Sympatholytic,Agents, Sympathetic-Blocking,Agents, Sympatholytic,Drug, Sympatholytic,Drugs, Sympatholytic,Effect, Sympatholytic,Effects, Sympatholytic,Sympathetic Blocking Agents

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