Biomedical subjects

R C Glen

Publications and source records attributed to R C Glen.

16 recordsLinked to original sources

PubMed1999

Synthesis and serotonergic activity of substituted 2, N-benzylcarboxamido-5-(2-ethyl-1-dioxoimidazolidinyl)-N, N-dimethyltryptamine derivatives: novel antagonists for the vascular 5-HT(1B)-like receptor.

The synthesis and vascular 5-HT(1B)-like receptor activity of a novel series of substituted 2, N-benzylcarboxamido-5-(2-ethyl-1-dioxoimidazolidinyl)-N, N-dimethyltryptamine derivatives are described. Modifications to the 5-ethylene-linked heterocycle and to substituents on the 2-benzylamide side chain have been explored. Several compounds were identified which exhibited affinity at the vascular 5-HT(1B)-like receptor of pK(B) > 7.0, up to 100-fold selectivity over alpha(1)-adrenoceptor affinity and 5-HT(2A) receptor affinity, and which exhibited a favorable pharmacokinetic profile. N-Benzyl-3-[2-(dimethylamino)ethyl]-5-[2-(4,4-dimethyl-2, 5-dioxo-1-imidazolidinyl)ethyl]-1H-indole-2-carboxamide (23) was identified as a highly potent, silent (as judged by the inability of angiotensin II to unmask 5-HT(1B)-like receptor-mediated agonist activity in the rabbit femoral artery), and competitive vascular 5-HT(1B)-like receptor antagonist with a plasma elimination half-life of approximately 4 h in dog plasma and with good oral bioavailability. The selectivity of compounds from this series for the vascular 5-HT(1B)-like receptors over other receptor subtypes is discussed as well as a proposed mode of binding to the receptor pharmacophore. It has been proposed that the aromatic ring of the 2, N-benzylcarboxamide group can occupy an aromatic binding site rather than the indole ring. The resulting conformation allows an amine-binding site to be occupied by the ethylamine nitrogen and a hydrogen-bonding site to be occupied by one of the hydantoin carbonyls. The electronic nature of the 2,N-benzylcarboxamide aromatic group as well as the size of substituents on this aromatic group is crucial for producing potent and selective antagonists. The structural requirement on the 3-ethylamine side chain incorporating the protonatable nitrogen is achieved by the bulky 2, N-benzylcarboxamide group and its close proximity to the 3-side chain.

Animals↗

PubMed1997

Development and validation of a genetic algorithm for flexible docking.

Prediction of small molecule binding modes to macromolecules of known three-dimensional structure is a problem of paramount importance in rational drug design (the "docking" problem). We report the development and validation of the program GOLD (Genetic Optimisation for Ligand Docking). GOLD is an automated ligand docking program that uses a genetic algorithm to explore the full range of ligand conformational flexibility with partial flexibility of the protein, and satisfies the fundamental requirement that the ligand must displace loosely bound water on binding. Numerous enhancements and modifications have been applied to the original technique resulting in a substantial increase in the reliability and the applicability of the algorithm. The advanced algorithm has been tested on a dataset of 100 complexes extracted from the Brookhaven Protein DataBank. When used to dock the ligand back into the binding site, GOLD achieved a 71% success rate in identifying the experimental binding mode.

Algorithms↗

PubMed1996

The inhibition of alpha-chymotrypsin predicted using theoretically derived molecular properties.

The structures and molecular properties of 95 aromatic and heteroaromatic ligands previously tested as reversible inhibitors of chymotrypsin catalysis have been calculated using AMl. The properties obtained have been used as input for multiple linear regression analysis and as descriptors for a back-propagation neural network to predict the binding affinity of alpha-chymotrypsin inhibitors. Using polarizability, molecular shape, electrostatic similarity, dipole moment, ClogP, and the diagonalized quadrupole moments of the ligands, correlation coefficients between calculated and experimental affinities of 0.96 for the training set and 0.89 for the test set were obtained using a neural network. The performance of the multiple linear regression was significantly worse, although useful QSARs were also obtained.

Binding Sites↗

PubMed1995

Synthesis and anticonvulsant activity of N-benzylpyrrolo[2,3-d]-, -pyrazolo[3,4-d]-, and -triazolo[4,5-d]pyrimidines: imidazole ring-modified analogues of 9-(2-fluorobenzyl)-6-(methylamino)-9H-purine.

Analogues of 9-(2-fluorobenzyl)-6-(methylamino)-9H-purine (1) containing isosteric replacements of the imidazole ring atoms were synthesized and tested for anticonvulsant activity. The pyrrolo[2,3-d]-, pyrazolo[3,4-d]-, and triazolo[4,5-d]pyrimidines were less active than 1 against maximal electroshock-induced seizures (MES) in rats when given po. The differences in anti-MES activity for these analogues was not explained by differences in pKa or lipophilicity. However, the four classes of heterocycles have distinctly different calculated electrostatic isopotential maps, which may be related to optimum anticonvulsant activity.

Animals↗

PubMed1995

Computer-aided design and synthesis of 5-substituted tryptamines and their pharmacology at the 5-HT1D receptor: discovery of compounds with potential anti-migraine properties.

The design and synthesis of a series of novel 5-substituted tryptamines with pharmacological activity at 5-HT1D and other monoamine receptors is described. Structural modifications of N- and C-linked (principally hydantoin) analogues at the 5-position were synthesized and their pharmacological activities were utilized to deduce significant steric and electrostatic requirements of the 5-HT1D and 5-HT2A receptor subtypes. Conformations of the active molecules were computed which, when overlaid, suggested a pharmacophore hypothesis which was consistent with the affinity and selectivity measured at 5-HT1D and 5-HT2A receptors. This pharmacophore is composed of a protonated amine site, an aromatic site, a hydrophobic pocket, and two hydrogen-bonding sites. A "selectivity site" was also identified which, if occupied, induced sensitivity for 5-HT1D over 5-HT2A in this series of molecules. The development and use of the pharmacophore models in compound design is described. In addition, the physicochemical constraints of molecular size and hydrophobicity required for efficient oral absorption are discussed. Utilizing the pharmacophore model in conjunction with the physicochemical constraints of molecular size and log DpH7.4 led to the discovery of 311C90 (6), a new selective 5-HT1D agonist with good oral absorption and potential use in the treatment of migraine.

Animals↗

PubMed1995

Molecular recognition of receptor sites using a genetic algorithm with a description of desolvation.

Understanding the principles whereby macromolecular biological receptors can recognise small molecule substrates or inhibitors is the subject of a major effort. This is of paramount importance in rational drug design where the receptor structure is known (the "docking" problem). Current theoretical approaches utilise models of the steric and electrostatic interaction of bound ligands and recently conformational flexibility has been incorporated. We report results based on software using a genetic algorithm that uses an evolutionary strategy in exploring the full conformational flexibility of the ligand with partial flexibility of the protein, and which satisfies the fundamental requirement that the ligand must displace loosely bound water on binding. Results are reported on five test systems showing excellent agreement with experimental data. The design of the algorithm offers insight into the molecular recognition mechanism.

Arabinose↗

PubMed1995

A genetic algorithm for flexible molecular overlay and pharmacophore elucidation.

A genetic algorithm (GA) has been developed for the superimposition of sets of flexible molecules. Molecules are represented by a chromosome that encodes angles of rotation about flexible bonds and mappings between hydrogen-bond donor proton, acceptor lone pair and ring centre features in pairs of molecules. The molecule with the smallest number of features in the data set is used as a template, onto which the remaining molecules are fitted with the objective of maximising structural equivalences. The fitness function of the GA is a weighted combination of: (i) the number and the similarity of the features that have been overlaid in this way; (ii) the volume integral of the overlay; and (iii) the van der Waals energy of the molecular conformations defined by the torsion angles encoded in the chromosomes. The algorithm has been applied to a number of pharmacophore elucidation problems, i.e., angiotensin II receptor antagonists, Leu-enkephalin and a hybrid morphine molecule, 5-HT1D agonists, benzodiazepine receptor ligands, 5-HT3 antagonists, dopamine D2 antagonists, dopamine reuptake blockers and FKBP12 ligands. The resulting pharmacophores are generated rapidly and are in good agreement with those derived from alternative means.

Algorithms↗

PubMed1995

A genetic algorithm for the automated generation of molecules within constraints.

A genetic algorithm has been designed which generates molecular structures within constraints. The constraints may be any useful function, for example an enzyme active site, a pharmacophore or molecular properties from pattern recognition or rule-induction analyses. The starting point may be random or may utilise known molecules. These are modified to 'grow' into families of structures which, using the evolutionary operators of selection, crossover and mutation evolve to better fit the constraints. The basis of the algorithm is described together with some applications in lead generation, 3D database construction and drug design. Genetic algorithms of this type may have wider applications in chemistry, for example in the design and optimisation of new polymers, materials (e.g. superconducting materials) or synthetic enzymes.

Algorithms↗

PubMed1994

A fast empirical method for the calculation of molecular polarizability.

A simple empirical method for the calculation of static molecular polarizability is described. The method is based on Slater's rules for the calculation of effective atomic nuclear shielding constants. The calculated molecular polarizabilities of a series of organic molecules correlated well (r = 0.98) with experimental measurements. Accurate calculated polarizabilities can be obtained rapidly by this method and may prove useful in deriving relationships between chemical structure and properties.

Electrochemistry↗

PubMed1994

Characterisation of the solution conformation of a cyclic RGD peptide analogue by NMR spectroscopy allied with a genetic algorithm approach and constrained molecular dynamics.

The solution conformation of a cyclic RGD peptide analogue, cyclo-(S,S)-2-mercaptobenzoate-arginine-glycine-aspartate-2-mer captoanilide, has been determined via two independent approaches for the searching of conformational space and identification of conformations consistent with NMR and CD spectroscopic data: (i) the use of a binary genetic algorithm and (ii) a molecular dynamics simulation. Inter-proton distances were obtained via analysis of cross-peak volumes from a two-dimensional ROESY NMR spectroscopy experiment at 600 MHz and were used as constraints for the computational calculations. The mercaptoanilide amide proton resonance chemical shift had a very small temperature coefficient, indicating that this proton was hydrogen-bonded. Circular dichroism data showed that, in solution, the torsion angle about the disulfide bond was negative, consistent with one of the distinct conformations around this bond in the 200 ps molecular dynamics simulation. The backbone conformations of the structures resulting from the two different approaches were very similar.

Amides↗

PubMed1993

Synthesis and platelet aggregation inhibiting activity of acid side-chain modified hydantoin prostaglandin analogues.

A series of hydantoin prostaglandin analogues, in which the hexamethylene moiety of the acid side chain was replaced by other spacing groups possessing either ether, sulphide and/or olefin functionality, were prepared and evaluated for platelet aggregation inhibiting activity. The 4-thia analogue 13*) proved to be the most potent inhibitor (ca. 22x PGE1) and the 3-thia- and 3-oxa-analogues, 6 and 10 respectively, are approximately equipotent with BW245C (ca. 14x PGE1). Z-olefinic analogues (e.g. 11) were usually more potent than their E-isomers (e.g. 12). Structure-activity relationships are discussed in detail.

Alprostadil↗

PubMed1993

Molecular recognition using a binary genetic search algorithm.

A genetic algorithm has been devised and applied to the problems of molecular similarity, pharmacophore elucidation, and determination of molecular conformation. The algorithm is based on a binary representation of molecular position and conformation. Using the genetic operators, crossover, mutation, and selection near optimum conformations and orientations of molecules may be determined which best-fit defined constraints. The constraints may be any useful function for example, intermolecular or intramolecular distances, electrostatic potential on a surface, or volume overlap. Problems with up to 30 degrees of freedom have been tackled successfully.

Algorithms↗

PubMed1992

Quantitative structure-metabolism relationships for substituted benzoic acids in the rat. Computational chemistry, NMR spectroscopy and pattern recognition studies.

An extensive set of computed molecular properties, both steric and electronic, have been calculated using molecular orbital and empirical methods for benzoic acid (1) and a congeneric series of substituted benzoic acids, i.e. 2-, 3- and 4-fluorobenzoic acids (2-4), 2-, 3- and 4-trifluoromethyl benzoic acids (5-7), 2-, 3- and 4-methylbenzoic acids (8-10), 4-amino benzoic acid (11), 2-fluoro-4-trifluoromethyl benzoic acid (12), 4-fluoro-2-trifluoromethyl benzoic acid (13), 3-trifluoromethyl-4-fluorobenzoic acid (14). We have monitored the urinary excretion profiles and determined the metabolic fate of compounds 2-7, 12-14 in the rat using high resolution 1H and 19F NMR spectroscopy. Corresponding data for compounds 1,8-11 are taken from the literature. In all cases phase II glucuronidation or glycine conjugation reactions dominated the metabolism of these compounds. Compounds 5, 7, 12, 13 have ester glucuronides as their major metabolites; the rest primarily form glycine conjugates. Compounds (1-12) have been classified according to their calculated physicochemical properties using pattern recognition methods and principal components maps have been used as a novel type of structure-metabolism diagram. The maps of compounds in the physicochemical property space served to separate the compounds into the two major classes which related to their principal metabolic fate in vivo, namely glucuronidation versus glycine conjugation. Compounds 13 and 14 were used as further probes of the property space, and dominant metabolic fates of glucuronidation and glycine conjugation, respectively, were predicted from the previous "training set map". The metabolic fate of compounds 1-14 can thus be classified according to a simple set of physicochemical rules. Investigation of the physicochemical properties which are important in distinguishing the metabolic fate of the compounds may give insight into key features of the drug-metabolizing enzyme active sites and hence provide information on basic mechanisms of benzoate metabolism.

Animals↗

PubMed1992

Inotropic polyazapentalene sulmazole analogues.

Aryl substituted 1H-imidazo[1,2-a]imidazole 8, imidazo[2,1-b]thiazole 9, 1,4-dihydroimidazo[4,5-d]imidazole 11, and 1(2),4-dihydroimidazo[4,5-c]pyrazoles 12-17 have been prepared. An X-ray crystallographic study confirmed the structure of 8 and showed this analogue to exist as the 1H-tautomer. These heterocycles were evaluated as inotropic agents and analogues 12, 15, and 17 found to display inotropic properties which were less potent in vitro, but more potent in vivo, than those of sulmazole. Structure-activity relationships are discussed.

Animals↗

PubMed1992

Applications of rule-induction in the derivation of quantitative structure-activity relationships.

Recently, methods have been developed in the field of Artificial Intelligence (AI), specifically in the expert systems area using rule-induction, designed to extract rules from data. We have applied these methods to the analysis of molecular series with the objective of generating rules which are predictive and reliable. The input to rule-induction consists of a number of examples with known outcomes (a training set) and the output is a tree-structured series of rules. Unlike most other analysis methods, the results of the analysis are in the form of simple statements which can be easily interpreted. These are readily applied to new data giving both a classification and a probability of correctness. Rule-induction has been applied to in-house generated and published QSAR datasets and the methodology, application and results of these analyses are discussed. The results imply that in some cases it would be advantageous to use rule-induction as a complementary technique in addition to conventional statistical and pattern-recognition methods.

Algorithms↗

PubMed1990

Inotropic "A" ring substituted sulmazole and isomazole analogues.

A series of "A" ring substituted sulmazole and isomazole analogues have been prepared and evaluated as inotropic agents. pKA's, protonation sites, and log P values were measured for selected compounds and their electronic properties were calculated. No simple correlation between inotropic activity and pKA, protonation site, or log P value was observed. However, in vitro inotropism did correlate with the calculated charge density of the "B" ring imidazo nitrogen atom. The 6-position of sulmazole appeared to be the most tolerant toward substituents, the 6-amino derivative 7 being a more potent inotrope than sulmazole itself. 4-Methoxyisomazole 13 had comparable in vivo inotropic properties to those of isomazole.

Animals↗