Theoretical Studies on Molecular Determinants for Recognition at H₃ Histamine Receptors

Abstract

A lek san d er P. M azurek and G ra żyna K arp iń ska Drug Institute, 30/34 Chehnska Street, 00-725 Warsaw, Poland Z. Naturforsch. 49c, 471-475 (1994); received February 17/May 5, 1994 Histamine, Methylhistamine, H3 Receptor, Molecular Orbital CalculationsThe determinants for recognition at H3 histamine receptors are considered. Findings based on quantum-chemical calculations suggest that H3 histamine receptor is less hydrophilic than the H2. The form most likely to be recognized by the H3 receptor is an intramolecularly hydrogen-bonded form of a-methylhistamine. Receptor environment and hydration effects of active form of histamine analogs are of crucial importance.

A Proton Relay Process as the Mechanism of Activation of the Histamine H3-Receptor Determined by1H NMR and ab Initio Quantum Mechanical Calculations

“…For antagonist 9 the population of III was the lowest while the total population of the folded conformation was the same as for compound 8 (Table ). This conformation−activity relationship is absent in nonpolar aprotic environment supporting the finding of Mazurek et al , that the biologically active form of the agonist is the monocation (which is also the most abundant form in solution at physiological pH (97%)) rather than the neutral form. However, a change from a polar protic environment (extracellular fluid mimic) to a more hydrophobic nonpolar aprotic (receptor mimic) environment favors conformer III.…”

“…The approach of Mazurek and Karpinska focuses on the major physicochemical properties of molecules that can discriminate between histamine H 2 - and H 3 -receptors. Calculations of energies at different conformations, hydrogen bond stabilization energies, and solvation energies of some histamine H 2 - and H 3 -receptor ligands at the STO-3G and 6-31G levels indicated that the form most likely to be recognized by the H 3 -receptor is a folded gauche conformation with an intramolecular hydrogen bond .…”

“…The approach of Mazurek and Karpinska focuses on the major physicochemical properties of molecules that can discriminate between histamine H 2 - and H 3 -receptors. Calculations of energies at different conformations, hydrogen bond stabilization energies, and solvation energies of some histamine H 2 - and H 3 -receptor ligands at the STO-3G and 6-31G levels indicated that the form most likely to be recognized by the H 3 -receptor is a folded gauche conformation with an intramolecular hydrogen bond . This is in accordance with combined ab initio calculations and Monte Carlo simulations of the conformational equilibrium for physiological existing forms of histamine ( 1 ) and R (α), S (β)-dimethylhistamine ( 3a ) by Nagy et al These calculations revealed that in aqueous solution 64% of histamine ( 1 ) is in the folded gauche conformation and that for both compounds the gauche N(τ)H conformation is more stable than the extended trans N(τ)H conformer by 8.4 kJ/mol .…”

Development of New Synthetic Reactions Using Hetero-Heavy Atoms and Their Application to Synthesis of Biofunctional Molecules

“…14). Indeed, several classical H 3 R antagonists, such as thioperamide and clobenpropit, 104) also have significant affinity for H 4 R. To investigate the physiological and pathophysiological roles of H 3 R and H 4 R, the development of a range of selective Theoretical calculations of histamine or some H 3 R-agonists have predicted the importance of an intramolecular hydrogenbonding between the cationic primary amine and the N atom of the imidazole, leading to a folded model A, and an extended model B as bioactive conformations of H 3 R-agonists was also reported 105,106) (Fig. 15).…”

Synthesis of 4(5)-[5-(Aminomethyl)tetrahydrofuran-2-yl- or 5-(Aminomethyl)-2,5-dihydrofuran-2-yl]imidazoles by Efficient Use of a PhSe Group: Application to Novel Histamine H3-Ligands1

“…Theoretical calculations of histamine or some H 3 -agonists have emphasized the importance of an intramolecular hydrogen bonding between the cationic primary amine and the N atom of the imidazole. , The 1 H NMR study on putative intramolecular hydrogen bonding for two H 3 -agonists was recently reported . However, the function of the intramolecular hydrogen bonding for activation of the H 3 -receptor has not been experimentally demonstrated.…”