A proposed topography for the histamine H2-receptor from structural AM1 calculations

Stamato, F. M. L. G.; Longo, E.; Perez, Marco A.; Guimaraes, Marcio A.P.; Smeyers, Yves G.

doi:10.1016/0166-1280(92)80093-2

Cited by 5 publications

(4 citation statements)

References 15 publications

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“…PCILO method results have indicated an open or extended backbone conformation for ranitidine 54. On the other hand, AM1 calculations have indicated a bent configuration for the ranitidine 34. X‐ray crystallographic results for ranitidine (ranitidine hydrogen oxalate) also indicate the folded conformation.…”

Section: Resultsmentioning

confidence: 99%

“…Histamine H2‐receptor antagonists (H2Ras) are a unique class of compounds 1–66. Pharmacologically they are characterized as a family by their ability to inhibit the secretion of gastric acid, and kinetically they are classified as a family by their similarity in absorption, distribution, and elimination.…”

Section: Introductionmentioning

confidence: 99%

“…On the other hand, the results of molecular orbital calculations of histamine of varying degrees of sophistication depend on the level of calculation, basis set, and system studied. At the semiempirical level, a variety of results could be obtained for several conformers/tautomers/protonation states with several methods (EHT 28, CNDO/2 29, 30, PCILO 31, MNDO 32, MINDO/3 33, AM1 34, etc.). Ab initio calculations with STO‐3G basis set 35 shows that the N 1 –H tautomer is the most stable trans neutral conformer; however, the results obtained by using the 3‐21G and 6‐31G basis sets 6 indicated that the N 3 –H tautomer is the most stable trans neutral conformer, whereas the N 1 –H tautomer is the most stable gauche neutral conformer.…”

Section: Introductionmentioning

confidence: 99%

“…The H2 receptors of histamine are responsible for a stimulation of the gastric secretions, the inhibition of the rat uterus contractions and the stimulation of isolated guinea pig atrium 37. The H2‐antihistaminergic agents, used in the treatment of the peptic ulcer disease, are conformationally very flexible molecules 34. Metiamide and ranitidine are known H2Ras, potent inhibitors of stimulated acid secretion in humans (pA2 = 6.02) 38–40.…”

Section: Introductionmentioning

confidence: 99%

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Theoretical ab initio study of ranitidine

Martins

Perez

Silva

et al. 2002

Int J of Quantum Chemistry

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ABSTRACT:The presence of a heterocyclic ring containing a basic center linked via a methylene chain to a substituted guanidine or thiourea polar side chain, such as found in the H2-antagonist metiamide, which has an imidazole heterocyclic ring, has often been identified as one of the requirements for H2-antagonist activity. In ranitidine, on the other hand, the imidazole ring is substituted for a furan ring, yielding a more active biological H2 antagonist. In this work, we have used the ab initio Hartree-Fock (HF) and second-order Møller-Plesset (MP2) methods in order to investigate the open and folded ranitidine conformations, of the type observed in metiamide. Five basis sets (3-21G, 3-21+G * * , 6-31G, 6-31+G * * , and 6-31+G * * ) were used in order to obtain fully optimized geometric parameters that indicated good agreement with the experimental crystallographic data. We have also investigated in this work the effects of solvents in both ranitidine and metiamide. Monocationic ranitidine was also investigated. All our results, indicate that, as in metiamide, the folded conformation is also preferred. We have investigated Mulliken and natural bond order (NBO) charge distributions, electrostatic and hydrogen bond effects on stabilizing the conformations and discussed the interactions of ranitidine with the biological receptor.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Theoretical ab initio study of ranitidine

Martins

Perez

Silva

et al. 2002

Int J of Quantum Chemistry

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Theoretical study of metiamide, a histamine H2 antagonist

Martins

Taft

Perez

et al. 1998

Int. J. Quant. Chem.

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ABSTRACT:The requirements for H -antagonist activity so far identified for most of 2 the known antagonists of histamine are the presence of a heterocyclic ring containing a basic center linked via a methylene chain to a substituted guanidine or thiourea polar Ž . side chain. Metiamide is a potent H antagonist pA2 s 6.06 . We have used the ab initio 2 Ž . Hartree᎐Fock HF method in order to study the conformational properties of the N -H 3 Ž U tautomers of metiamide molecule and histamine monocation. Three basis set the 3-21G , UU UU . 6-31G , and 6-31qG were used, the results compared, and the geometric parameters fully optimized. Our results indicate the preference of metiamide for a folded conformation with an intramolecular hydrogen bonding between the imidazole ring and one of the NH groups. The optimized geometrical parameters and charge distributions of Ž . both molecules, using the Mulliken, and natural bond order NBO analysis, are given and discussed.

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