The computational design of test compounds with potentially specific biological activity: Histamine-H2 agonists derived from 5-HT/H2 antagonists

SummaryThe previously proposed models for the recognition and activation of 5-HT and histamine-H2 receptors, which were employed to explain the antagonist activity of LSD at both of these receptors, as well as the selective antagonism for H2 receptors by SKF-10856 and 9,10-dihydro-LSD, are used herein to design a compound to test the H2-receptor model. The design strategy attempts to construct a compound with potentially selective H2 agonism. The design scheme maintains features which were previously used to explain selective recognition of SKF-10856 and 9,10-dihydro-LSD as well as reintroduces the chemical features proposed to be responsible for H2 activation. The existence of the H2 recognition and activation features in the proposed compound is verified, in a previously proposed model, by computational studies of the molecular electrostatic potentials and shifts in the tautomeric preference.

[1]  R. Osman,et al.  Molecular determinants for binding of methylenedioxytryptamines at 5-HT/LSD receptors , 1981 .

[2]  H Weinstein,et al.  QUANTUM CHEMICAL STUDIES ON MOLECULAR DETERMINANTS FOR DRUG ACTION * , 1981, Annals of the New York Academy of Sciences.

[3]  Peter Politzer,et al.  Chemical Applications of Atomic and Molecular Electrostatic Potentials: "Reactivity, Structure, Scattering, And Energetics Of Organic, Inorganic, And Biological Systems" , 2013 .

[4]  Eamonn F. Healy,et al.  Development and use of quantum mechanical molecular models. 76. AM1: a new general purpose quantum mechanical molecular model , 1985 .

[5]  H Weinstein,et al.  Theoretical studies on the activation mechanism of the histamine H2-receptor: the proton transfer between histamine and a receptor model. , 1986, Molecular pharmacology.

[6]  Harel Weinstein,et al.  Electrostatic Potentials as Descriptors of Molecular Reactivity: The Basis for Some Successful Predictions of Biological Activity , 1981 .

[7]  C. Chothia,et al.  Molecular Structure of LSD , 1972, Science.

[8]  R. Osman,et al.  A molecular theory of recognition and activation at a 5-HT receptor based on a quantum chemical approach to structure activity relationships. , 1985, Clinical physiology and biochemistry.

[9]  M. Shinitzky,et al.  Complexes between Indole and Imidazole Derivatives of the Charge-Transfer Type , 1968 .

[10]  R. Osman,et al.  A theoretical investigation of histamine tautomerism. , 1984, Journal of medicinal chemistry.

[11]  Sid Topiol,et al.  The deletion model for the origin of receptors , 1987 .

[12]  R. Osman,et al.  A molecular model for activation of a 5-hydroxytryptamine receptor. , 1987, Molecular pharmacology.

[13]  C. Strader,et al.  A single amino acid substitution in the beta-adrenergic receptor promotes partial agonist activity from antagonists. , 1989, The Journal of biological chemistry.

[14]  S. Topiol.  Comparison of the use of the MNDO and MINDO/3 methods with ab initio methods to study tautomerism in histamine, 2‐ and 4‐methylhistamine , 1987 .

[15]  J. Pople,et al.  Self‐Consistent Molecular‐Orbital Methods. I. Use of Gaussian Expansions of Slater‐Type Atomic Orbitals , 1969 .

[16]  H. Weinstein,et al.  Molecular determinants for the agonist activity of 2-methylhistamine and 4-methylhistamine at H2-receptors. , 1986, Journal of medicinal chemistry.