New activation model for the histamine H2 receptor, explaining the activity of the different classes of histamine H2 receptor agonists.

Recently we developed amthamine [2-amino-5-(2-aminoethyl)-4-methylthiazole]. This cyclic analogue of dimaprit proved to be the most potent and selective histamine H2 receptor agonist of a series of substituted 4- or 5-(2-aminoethyl)thiazoles. Quantum chemical studies on histamine (N pi-H tautomer), dimaprit, and amthamine revealed that, based upon geometries of molecular electrostatic potentials, it is likely that these agonists accept a proton from the proton-donating receptor site on their double-bonded (heteroaromatic) nitrogen atoms. In contrast to reported models, this new model is able to accommodate and explain the agonistic activities of all known (including nontautomeric) histamine H2 receptor agonists. Quantitative structure-activity relationship studies with a series of substituted histamine derivatives and heterocyclic analogues support the presented model, in which the monocations in extended conformation interact with the receptor surface; their affinities correlate with the proton association constants of the heteroaromatic nuclei. The negatively charged anchoring site for the ethylammonium side chain of these agonists in this model is a functional group with a pKa value of 4.17.

Histamine H2-receptor agonists. Synthesis, in vitro pharmacology, and qualitative structure-activity relationships of substituted 4- and 5-(2-aminoethyl)thiazoles.

It is well known that both histamine and dimaprit show moderate histamine H2-receptor agonistic activities on the guinea pig right atrium. Quantum chemical calculations on these two compounds showed similarities in electron distributions and molecular electrostatic potentials (MEP's), which could be extended to rigid analogues [2-amino-5-(2-aminoethyl)thiazoles] of the latter structure. On the base of these results a series of substituted 4- and 5-(2-aminoethyl)thiazoles was synthesized applying small alkyl substitution variations as reported for histamine. 2-Amino-5-(2-aminoethyl)-4-methylthiazole (Amthamine) proved to be the most potent full histamine H2-receptor agonist on the guinea pig right atrium, being with a pD2 value of 6.21 slightly more potent than histamine. This compound shows no affinity for H1-receptors and is a full but weak agonist on the histamine H3-receptor with a pD2 value of 4.70, thus showing a marked specificity for histamine H2-receptors. In the 5-(2-aminoethyl)thiazole series the presence of a 2-amino substituent proved to be not essential for stimulation of the histamine H2-receptor, leading to the important conclusion that in contrast to histamine, for this series, acceptance of a proton by the thiazole nucleus of the agonist from the active site of the receptor is sufficient for the stimulation of the histamine H2-receptor.

4- or 5- (omega-aminoalkyl) thiazoles and derivatives; new selective H2-receptor agonists.

It is well known that both histamine and dimaprit show moderate H2-receptor agonistic activity (guinea pig right atrium). Quantum chemical calculations indicated that 2-aminothiazole derivatives that might be regarded as cyclic dimaprit analogues, should possess H2-receptor agonistic activity as well. In the present study a series of 4- or 5-(omega-aminoalkyl) thiazoles has been synthesized, showing a moderate to strong H2-receptor agonistic activity as compared to histamine whereas no activity on H1- and H3-receptors could be detected. In contrast to histamine and derivatives, which are supposed to "trigger" the H2-receptor via a tautomeric shift involving two protons viz. one proton of the active site of the receptor and one proton of the heteroaromatic ring system, the thiazole derivatives seem to stimulate the H2-receptor via a one proton mechanism. In a series of impromidine analogues the 3- [4(5)-imidazolyl]propyl moiety was replaced by the more H2-receptor specific 3-(4- or 5-thiazolyl)propyl fragment resulting in potent and selective full H2-receptor agonists.

Studies on the active molecular species of the H2 receptor antagonists cimetidine and mifentidine.

The N'-(4-1H-imidazol-4-ylphenyl)formamidines were recently introduced as a new class of active H2 antagonists; the authors of the compounds (Donetti et al. of de Angeli, Italy) have suggested that these compounds interact with the H2 receptor through their monocations. This is at variance with the model proposed for cimetidine by the SK&F (Smith Kline & French, UK) group who proposed the neutral molecule as the species active at the H2 receptor. In the present study we have investigated the issue whether the neutral or charged species is the active one by measuring the pA2 values of mifentidine and cimetidine at different pH values. Changing the pH will influence the species equilibria of both compounds and thereby affect their activity. The activity changes measured for both compounds are consistent with the proposition that cimetidine as well as mifentidine elicit their activity through their neutral species.

Determination of formation constants of copper(II) complexes of Adler medium components with a solid-state copper(II) ion-selective electrode.

A general method for the determination of overall conditional formation constants of copper(II) complexes of mycoplasma growth medium (Adler) constituents together with the protonation constants of the complexing ligands was developed. In Adler medium a total of 0.204 +/- 0.004 molar copper binding sites proved to be present with log beta 2 = 8.14 +/- 0.05 (mu = 0.11) and log Ka = 6.14 +/- 0.004. Conditional overall formation constants were calculated at various pH values. Free copper(II) ion concentrations were calculated as a function of the total added amount of copper(II) and pH. The consequences of these findings for the determination of the growth inhibition of mycoplasmas by copper complexes of 2,2'-bipyridyl analogues are stressed.