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R Osman

Publications and source records attributed to R Osman.

67 records · Page 4Linked to original sources
PubMed1985

A molecular theory of recognition and activation at a 5-HT receptor based on a quantum chemical approach to structure activity relationships.

The study of structure activity relationships (SAR) is based on the delineation of the causal relationships between the properties of molecules and the observed responses evoked by the interaction of these molecules with biological systems. The methods of theoretical and quantum chemistry describe accurately the molecular properties that are determined by molecular structure and provide a rigorous link between structure and activity. We study the molecular events in the pharmacological mechanism of drugs interacting with the receptor of 5-hydroxytryptamine (5-HT, serotonin) by defining the elements of recognition and by analyzing the changes induced in a molecular model for the receptor. These steps define the relationship between the properties of the drugs and their ability to be recognized and cause the activation of the receptors. Consequently, our quantum chemical studies of drug-receptor interactions explain the selectivity of receptors and the molecular determinants for agonism and antagonism on the 5-HT receptor.

Imidazoles↗
PubMed1984

The two-modes-of-binding model for partial agonism and the design of partial agonists.

A model of drug action is developed for a drug which can bind in two modes to a given receptor: an agonist mode which elicits a response and an antagonist mode which does not. It is shown that this combination of agonist and antagonist binding, which is tantamount to self-antagonism, can lead to agonist, partial agonist or antagonist behavior. The proposed two-modes-of-binding model has applications to the design of partial agonists. Finally, partial agonism arising from two modes of binding is indistinguishable from partial agonism occurring by two-state model mechanisms using experimental equilibrium studies.

Models, Biological↗
PubMed1984

A theoretical investigation of histamine tautomerism.

Geometry optimizations of the structures of histamine (neutral and monocation) in the N(3)-H and N(1)-H tautomeric forms were performed at the ab initio Hartree-Fock level with the STO-3G basis set. Values of the structural parameters and their changes upon protonation and/or tautomerization are in good agreement with data from X-ray crystal-structure analysis of histamine and several analogues. Earlier predictions of the tautomeric preference from calculations using frozen geometries based on crystal-structure data are confirmed by calculations of energies of histamine in the fully optimized geometries with both the STO-3G and LP-3G basis sets and by comparisons of the minima in the molecular electrostatic potentials of the two tautomers. These results support a previously proposed model for the activation of the histamine H2 receptor.

Histamine↗
PubMed1984

Kinetic characterization of the rabbit aorta contractile response to an alpha adrenergic agonist.

The alpha-1 adrenergic response of the rabbit aorta to phenylephrine (PE) was separated into a phasic and a tonic response by virtue of their different dependence on extracellular [Ca++]. The kinetics of each response was characterized with respect to its dependence on [PE] and [Ca++]. The phasic response is independent of extracellular calcium and has a rapid onset followed by a first order decay. Although its maximal attainable response is saturable with respect to [PE] and [Ca++], its rate constant for onset does not depend on the concentration of calcium in the preincubation buffer. We were unable to show that this rate constant for onset is saturable with respect to [PE]. This suggests that the rate-determining step of the phasic response is the diffusion-controlled formation of the drug-receptor complex. The tonic response depends on extracellular calcium, shows first order kinetics of onset and reaches a steady-state level of contraction that is saturable with respect to [PE] and extracellular [Ca++]. The rate constant for the generation of the tonic response depends on [PE] in a saturable manner and linearly on extracellular [Ca++]. This suggests that the rate-determining step could be the activation of a hypothetical effector by the drug-receptor complex. The activated effector would enable the transport of calcium ions into the cell. The kinetic studies predict that the efficacy of a drug in this system is the maximal rate of activation of the effector by the drug-receptor complex.

Adrenergic alpha-Agonists↗
PubMedDate not supplied

On the structural and mechanistic basis of function, classification, and ligand design for 5-HT receptors.

We review our results from the first computational simulations of a mechanism by which ligands can activate a 5-HT1A receptor, and relate the findings to information on the structure and function of the authentic receptor. The computational exploration of the recognition and activation mechanisms is carried out inside a protein selected as a model for the receptor based on cognate physicochemical and experimental data. A similar approach is applied to the 5-HT2 receptor. The interaction mechanisms at the two 5-HT receptor subtypes differ in the nature of the forces determining ligand-receptor interactions and the types of receptor activation mechanisms they entail. The main molecular property related to recognition at 5-HT1A receptors was shown to be the directional character of the electrostatic potential generated by the ligands in the molecular region corresponding to the indole in 5-HT. The corresponding recognition site was shown to have properties of a positively-charged (imidazolium) form of the side chain of a His residue. The mechanism of recognition at the 5-HT1A receptor was shown to be electrostatic, and conducive to a triggering of the receptor response through the change in the electronic structure of the imidazolium recognition site when it interacts with an activating ligand (agonist). This effect was shown to induce a proton transfer from the ring to a neighboring residue to which it can be hydrogen-bonded in the resting state. We show how this model for recognition and activation defines in molecular terms the mechanisms underlying the classical pharmacologic properties of agonists, partial agonists, and antagonists. The molecular correlates of pharmacologic efficacy emerge from the calculations of the effect of the ligands on the barriers for proton transfer, and on the energy drive for the proton transfer reaction. A different model is proposed for selective recognition at the 5-HT2 receptors, based on structural details of 5-HT-binding peptides. The recognition site is considered to consist of two aromatic residues separated by a hydrophilic residue. In contrast to the model for 5-HT1A, the recognition is based on the interaction of neutral molecules and the stabilization is provided by dispersion forces. The resulting activation mechanism is based on a structural rearrangement. These detailed descriptions of elements in the ligand-receptor interactions at the two receptor subtypes lead to a new basis for rational design of receptor-selective compounds with predetermined efficacy.

Animals↗
PubMedDate not supplied

Kinetics of response and drug action.

Vascular smooth muscle tone is modulated in vivo by the functional interaction of a variety of vasoconstrictor and vasodilator stimuli. Endogenous substances (e.g., epinephrine) acting on smooth muscle, simultaneously activate alpha-adrenergic receptors (alpha-AR) eliciting contraction and beta-adrenergic receptors (beta-AR) which relax the muscle. This study characterizes the beta-adrenergic response in the isolated rabbit aorta precontracted with phenylephrine (PE) or serotonin (5-hydroxytryptamine [5-HT]). The beta-adrenergic agonist isoproterenol (ISO) produces a biphasic response that is composed of a rapid relaxation followed by a slower regaining of tension identified as desensitization. An exploratory kinetic model that describes both relaxation and desensitization as first order processes provides a good description of the experimental data. The five parameters used to describe the ISO response are: the observed rate constants for relaxation and desensitization (krel and kdes), the fractional magnitudes of the changes in tension for the two processes (R/C) and D/R), and the observed delay in the onset of the desensitization response, td. The krel and R/C were dependent on concentration of ISO in a saturable manner in rings precontracted with either 1 mumol/L PE or 1 mumol/L 5-HT and inversely related to the concentration of the contractile agonist. Yet, although the degree of fractional relaxation in the presence of PE covered the full range, that of 5-HT extended over a range of 20%. This behavior leads to the conclusion that the functional interaction between the contractile and relaxing stimuli is non additive. No dependence on the concentration of ISO was observed for D/R, kdes, and td.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Analysis of the molecular electrostatic potential for the prediction of N-oxidation and biological activity of substituted pyridines.

Comparative studies on the reactivity of the heterocyclic nitrogen were carried out for pyridine and its three monosubstituted derivatives 2-aminopyridine (2-AP), 3-aminopyridine (3-AP), and 4-aminopyridine (4-AP) to reveal the structural basis for the differences in their susceptibility to N-oxidation. Molecular orbital calculations were performed to obtain the wave functions for the calculation of the molecular electrostatic potentials (MEP) generated by the molecules. The comparison of the reactivity of the cyclic nitrogen, evaluated from the depth and accessibility of the minimum in the MEP, indicates that the nitrogen in 4-AP will be most susceptible to protonation and will be the most protected from N-oxidation at physiological pH values. The MEP map for 2-AP reveals the smallest minimum in the series of compounds and a considerable reduction in the accessibility of the region near the cyclic nitrogen caused by the proximal substitution. On this basis, 3-AP becomes the most likely derivative to form the ring N-oxide. Comparison of the conclusions from the MEP analysis with available data from bioassays suggests that the mechanism responsible for the genotoxic effects of the chemicals, where only 3-AP is active, is very different from the mechanism for systemic toxicity where 3-AP is the least active, and 4-AP is most active probably due to its channel blocking properties. As the mechanisms for the biological activities of the N-oxide metabolites become clear, reliable predictions of the toxicity of the pyridines should become possible based on such reactivity characteristics.

Animals↗