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Biomedical subjects

Y C Martin

Publications and source records attributed to Y C Martin.

At least 19 recordsLinked to original sources
PubMed1991

Direct prediction of dissociation constants (pKa's) of clonidine-like imidazolines, 2-substituted imidazoles, and 1-methyl-2-substituted-imidazoles from 3D structures using a comparative molecular field analysis (CoMFA) approach.

The applicability of a comparative molecular field analysis (CoMFA) method to reproduce and predict the pKa values of 28 clonidine-like imidazoline analogues and 16 2-substituted imidazoles has been investigated with the GRID force field. Molecular fields calculated with an H+ probe and AM1 partial atomic charges produced a correlation with a small standard deviation and a high correlation coefficient with cross validation. It was concluded that the CoMFA treatment of electrostatic effects is suitable for predicting pKa values and thus for the examination of the electronic effects in 3D quantitative structure-activity relationships.

Clonidine↗
PubMed1990

Quantitative structure-activity relationships of inhibitors of immune complex-induced inflammation: 1-phenyl-3-aminopyrazoline derivatives.

Quantitative structure-activity relationships (QSAR) of the 1-phenyl-3-aminopyrazoline analogues as inhibitors of immune complex-induced inflammation have been studied. The correlation suggests that the overall size of the phenyl substituents are of importance, and bulky groups have negative effects on potency. The negative steric effects are gradually increased from ortho to meta to para positions. The negative steric effects were sometimes altered by the electronic effects of the substituents. Electron-releasing groups on the phenyl ring increased potency, while electron-withdrawing groups decreased it. Ortho substituents, however, have unaccounted for additional deleterious effects described here with an indicator variable. The octanol-water partition coefficient (log P) and dissociation constants (pKa) of the 1-(m-trifluoromethylphenyl)-3-aminopyrazoline analogue have been experimentally determined.

Animals↗
PubMed1990

Inhibitors of immune complex-induced inflammation: 5-substituted 3-[1-(2-benzoxazolyl)hydrazino]propanenitrile derivatives.

A number of 5-substituted 3-[1-(2-benzoxazolyl)hydrazino]propanenitrile analogues have been studied as inhibitors of the rat pleural reverse passive Arthus reaction, and quantitative structure-activity relationships (QSAR) of these analogues have been examined. The QSAR equations indicate that hydrophilic substituents at the 5-position produce more potent compounds, while electron-releasing groups decrease activity. The results supplement QSAR data we previously obtained from the dermal reverse passive Arthus reaction.

Animals↗
PubMed1989

Inhibitors of immune complex-induced inflammation: 3-[1-(2-benzoxazolyl)hydrazino]propanenitrile derivatives.

The octanol-water partition coefficients (log P) and the dissociation constants (pKa) of 3-[1-(2-benzoxazolyl)hydrazino]propanenitrile analogues have been determined, and quantitative structure--activity relationships (QSAR) of the analogues as inhibitors of immune complex-induced inflammation have been studied. A significant correlation is observed between log P and pi substituent constants, and between pKa and inductive-field (F) and resonance (R) constants. The QSAR equations indicate that smaller substituents both at the 5-position and/or at the side chain tend to make the compound more potent, while an electron-withdrawing group at the side chain tends to make the compound less potent. The predicted potencies of 14 of 18 additional monosubstituted and all six disubstituted analogues agree reasonably well with the observed activities.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1989

ALADDIN: an integrated tool for computer-assisted molecular design and pharmacophore recognition from geometric, steric, and substructure searching of three-dimensional molecular structures.

ALADDIN is a computer program for the design or recognition of compounds that meet geometric, steric, and substructural criteria. ALADDIN searches a database of three-dimensional structures, marks atoms that meet substructural criteria, evaluates geometric criteria, and prepares a number of files that are input for molecular modification and coordinate generation as well as for molecular graphics. Properties calculated from the three-dimensional structure are described by either properties calculated from the molecule itself or from the molecule as compared to a reference molecule and associated surfaces. ALADDIN was used to design analogues to probe a bioactive conformation of a small molecule and a peptide, to test alternative superposition rules for receptor mapping of the D2 dopamine receptor, to recognize unexpected D2 dopamine agonist activity of existing compounds, and to design compounds to fit a binding site on a protein of known structure. We have found that series designed by ALADDIN show much more subtle variation in shape than do those designed by traditional methods and that compounds can be designed to be very close matches to the objective.

Binding Sites↗
PubMed1988

MENTHOR, a database system for the storage and retrieval of three-dimensional molecular structures and associated data searchable by substructural, biologic, physical, or geometric properties.

MENTHOR is a database system for the storage and retrieval of three-dimensional coordinate and charge information on molecules as well as of traditional biological and physical properties. Our molecular graphics system retrieves from MENTHOR structural information in individual molecules and receptor map/macromolecular binding site hypotheses. Substructural searches of MENTHOR are used to find starting coordinates for molecular modeling and traditional database searches of MENTHOR identify compounds for which modeling is needed. It also forms the data to be searched with ALLADDIN, our substructure/geometric search program. MENTHOR expedites molecular modeling by organizing previous work and facilitating transmission of information between individuals. Examples from modeling of D-2 receptor agonists are shown.

Drug Design↗
PubMed1988

Differentiation of alpha-adrenergic receptors using pharmacological evaluation and molecular modeling of selective adrenergic agents.

Subtypes of alpha adrenergic receptors were studied using selective adrenergic agonists. A-53693, A-54741, and related compounds were evaluated for their affinity for alpha receptor subtypes using radioligand binding techniques. Efficacy and potency were also evaluated using in vitro bioassays of alpha-1 receptors in rabbit aorta smooth muscle and alpha-2 receptors in the phenoxybenzamine-pretreated canine saphenous vein. Active and inactive compounds were then submitted for computer-assisted molecular modeling evaluation to ascertain the structural requirements for optimal potency and selectivity. Rigid catecholamines such as A-53693 display a high degree of selectivity for alpha-2 compared to alpha-1 receptors, probably because of the unique regions of space at the ligand binding site occupied by active compounds. Imidazolines such as A-54741 also interact with extremely high affinity and potency for alpha-2 receptors, and to a lesser extent at alpha-1 receptors. The spatial domains occupied by phenethylamines and imidazolines differ, each having unique regions of permissable space at alpha receptors. Compounds such as A-53693 and A-54741 are extremely useful probes of the molecular interactions of alpha agonistic compounds which will help in the design of even more selective drugs for alpha adrenergic receptors.

Adrenergic alpha-Agonists↗
PubMed1987

Structural requirements for the inhibition of 5-lipoxygenase by 15-hydroxyeicosa-5,8,11,13-tetraenoic acid analogues.

The structural requirements for inhibition of RBL-1 (rat basophilic leukemia) 5-lipoxygenase by 15-hydroxyeicosa-5,8,11,13-tetraenoic acid (15-HETE, 1) were studied by systematic chemical modifications of the molecule at the hydroxyl and carboxyl groups, the double bonds, and the carboxylate and omega side chains. The most potent inhibitors were analogues that contained a 5,8-cis,cis-diene system and acted as alternate substrates for the enzyme. However, several analogues in which the 5,8-diene had been reduced were also found to inhibit the enzyme. Inhibition of 5-lipoxygenase by 15-hydroxyeicosa-11,13-dienoic acid (15-HEDE) analogues was optimal in compounds that generally contained a free carboxyl group, a carboxylate side chain of nine carbons, an omega side chain of five or six carbons, a cis,trans- or trans,cis-11,13-diene or 11,13-diyne system, and a 15-hydroxyl group. Conversion of 15-HEDE to its 16-membered lactone reduced but did not eliminate 5-lipoxygenase inhibitory activity. In contrast, a 3- to 10-fold enhancement of activity occurred when 5,15-diHETE (58) or 5-HETE (56) were cyclized to their respective delta-lactones. Molecular modeling of 15-HEDE analogues, modified in the C11-C15 region, showed that inactive analogues protrude into regions in space not occupied by active analogues. These structural studies indicate that multiple regions are important for 5-lipoxygenase inhibition by both 15-HETE and 15-HEDE analogues and that no single region plays a predominant role in inhibition.

Animals↗
PubMed1986

Comparison of calculated versus measured partition coefficients of some phenyl beta-D-glucopyranosides.

Experimentally determined octanol-water partition coefficient values of substituted phenyl beta-D-glucopyranosides are compared with the calculated values using the computer program CLOGP. The systematic deviation of the calculated values from the measured ones in this series suggests that caution is required when calculations are performed on classes of compounds where many of the partition coefficients have not been experimentally determined.

Glucosides↗
PubMed1986

Conformationally defined adrenergic agents. 2. Catechol imidazoline derivatives: biological effects at alpha 1 and alpha 2 adrenergic receptors.

The synthesis and pharmacology of 2-(5,6-dihydroxy-1,2,3,4-tetrahydro-1-naphthyl)imidazoline (A-54741, 4), a very potent alpha-adrenergic agonist, are described. The change in biological activity resulting from variation of the carbocyclic ring size of 4 from four through seven members (2-5) is presented, as well as an explanation that accounts for this change in activity by considering the "exactness of fit" of these compounds to both the alpha 1- and alpha 2-adrenergic receptors. Compound 4 was found in vitro to be a full agonist with greater potency at the alpha 2 receptor (ED50 norepinephrine (NE)/ED50 4 = 188 +/- 22) than at the alpha 1 receptor (ED50 NE/ED50 4 = 13 +/- 2).

Adrenergic alpha-Agonists↗
PubMed1985

[(Aminomethyl)arloxy]acetic acid esters. A new class of high-ceiling diuretics. 3. Variation in the bridge between the aromatic rings to complete mapping of the receptor.

Continued structural evaluation of the [(aminomethyl)aryloxy]acetic ester diuretics has produced a series of compounds in which the functional group that bridges the two aromatic rings has been varied. Diuretic screening of these analogues in rats indicates that the keto group can be effectively replaced with an ether or thio ether function with a slight increase in potency, whereas the methylene and sulfoxide linking groups lead to diminished saluretic potency. Replacement with either -SO2-, -COCO-, -CH2O-, -CONH- or direct bond results in a loss of activity. Although the series was designed according to QSAR criteria, the traditional linear free-energy properties of these compounds do not correlate with diuretic potency. However, conformational analysis of the series by potential energy calculations indicates that all active compounds have an accessible conformation that matches the bridge atom-carboxylate distance of the very potent dihydrobenzofuran analogue 56. Conformational calculations of several compounds in which the aminomethyl group was varied suggests that the active conformation is probably a low-energy conformation. Consideration of rotation about the bridge could not distinguish between two possible orientations of the aminomethyl ring in the active conformation. However, there is a quantitative negative linear correlation between diuretic potency and the protrusion into space of the group that bridges the two aromatic rings.

Animals↗
PubMed1976

Theoretical model-based equations for the linear free energy relationships of the biological activity of ionizable substances. 1. Equilibrium-controlled potency.

Because of the ambiguities of how to treat ionization in empirical equations which relate biological activity to partition coefficient by use of a (log P)2 term, a theoretical approach to the problem is proposed. Based on a simplified view of assays of potency following in vitro or continuous infusion administration of drugs, equations have been derived from a combination of mass law, equilibrium, and extrathermodynamic assumptions. In general form the equations which relate potency to partition coefficient (P) and degree of ionization (alpha) are the following. If the neutral form reacts with the receptor, log (1/C) =-log [1 + SIGMAM(DIPci) + sigman[aj/Pb(1-alpha4y]] + X. If the ionic form reacts with the receptor, log (1/C) =-log [1 + (1 - Alphan)/(alphan)[sigmam(diPci) + sigman[aj/Pb(1-alphaj)]]] + X. In this generalized model there are m nonaqueous compartments and n aqueous compartments of different pH. The parameters a, b, c, and d can be interpreted in terms of the model. The shape of the log (1/C) vs. log P curve may be asymptotic, linear, or composed of two portions of unequal slope which meet at an optimum or a bend. With the use of these equations it is possible to examine whether the ion or the neutral form is the active species and whether there is hydrophobic bonding to the receptor and/or an inert compartment. The models may be further extended to include terms other than log P and alpha.

Chemical Phenomena↗
PubMed1975

Regression analysis of the relationship between physical properties and the in vitro inhibition of monoamine oxidase by propynylamines.

Regression analysis of the potency of inhibition of monoamine oxidase by 47 propynylamines revealed that there are three determinants of inhibitory potency: (1) the smallest substituent on the nitrogen must be methyl or hydrogen in order for any activity to be observed; (2) potency is parabolically related to pKa-the optimum pKa is 6.2; and (3) ortho-substituted benzylamine analogs are ten times more potent than predicted on the basis of pKa values. The optimum pKa cannot be explained by differences in fraction ionized but rather in terms of the multistep sequence whereby these compounds inhibit MAO. A very slight positive effect of hydrophobicity on potency was found. The potency of several analogs not included in the original analysis was predicted.

Alkynes↗