Quantitative structure-activity relationships in a set of thiazolidin -4-ones acting as H1-histamine antagonists.

A series of 2-(3- and 4-substituted phenyl)-3-[3-(N, N-dimethyl-amino)propyl]-1,3-thiazolidin-4-ones acting as H1-antihistaminics was investigated with a combined Hansch-CoMFA approach. The substituents at the 3- and 4-positions of the phenyl ring have been described through steric, electronic and hydrophobic parameters and correlated with pA2 values. The obtained quantitative models suggest that affinity to the receptor is promoted by hydrophobic and small 4-substituents and by 3- and 4-substituents generating a positive electrostatic potential towards a complementary receptor region.

Effects of variable selection on CoMFA coefficient contour maps in a set of triazines inhibiting DHFR.

An example of a CoMFA study is described with the aim to discuss one of the major problems of this 3D QSAR method: lack of variable selection. It is shown that the use of nonrelevant energy parameters might produce CoMFA contour maps which poorly reflect the actual nature of the binding site and are in part statistical artefacts. The data set employed in our analysis comprises triazine inhibitors of dihydrofolate reductase (DHFR), isolated from chicken liver, which have already been the object of a QSAR study by other authors.

Synthesis and neurokinin antagonist activity of 2-benzylidene- and 2-benzyl-3-benzylamino quinuclidines.

Molecular modeling studies based on the potent NK-1 antagonist CP-96,345 led us to the identification of some 2-benzylidene- and 2-benzyl-3-benzylaminoquinuclidine derivatives as potential antagonists at the NK receptor subtypes. The synthesized compounds, whose Z/E isomerism has been defined by X-ray analysis, show only moderate potency on the three neurokinin receptors. The possible reasons of the low potency exhibited by the tested compounds are discussed.

Synthesis and muscarinic receptor binding profiles of antagonist benzotriazole derivatives.

A series of benzotriazole derivatives were synthesized and tested in order to determine their activities for muscarinic receptor subtypes (M1, M2 and M3). Binding affinities were measured as KI values by competition against [3H]-N-methylscopolamine in rat cortex, atria and ileum. Pharmacological in vitro tests were performed on isolated tissue preparations (rabbit vas deferens, guinea pig atria and ileum); the compounds showed antimuscarinic activity.

Use of the hydrogen bond potential function in a comparative molecular field analysis (CoMFA) on a set of benzodiazepines.

The results of the GRID-Comparative Molecular Field Analysis (CoMFA) were compared with those of the SYBYL-CoMFA in a study of benzodiazepines. The results demonstrate that the hydrogen bonding function using the GRID H2O probe in a CoMFA can successfully describe the hydrophobic effects of substituents without any bias or preconcept of their effects in the development.

Relationships between octanol-water partition data, chromatographic indices and their dependence on pH in a set of beta-adrenoceptor blocking agents.

A thorough investigation on the dependence of octanol/water distribution coefficients (log D) of basic and amphiprotic beta-blocker drugs on pH and pKa values has been carried out. An attempt is made to clarify the factors which govern the chromatographic parameters (log k') in reversed-phase high performance liquid chromatography (RPLC) in terms of chemical structure and of distribution coefficients. The correlations between log D and log k' of different compounds show that the bulkiness and the branching of nitrogen substituent are controlling factors in RPLC measurements.

Toward a quantitative comparative toxicology of organic compounds.

Correlation equations between logP (P = octanol water partition coefficient) and the biological activity of alcohols has been derived for 101 examples on all sorts of systems, from simple proteins to whole animals. This provides an overview of the toxic nature of hydrophobic compounds which can be used as a basis for comparison of more complex chemicals. About 100 examples of the hydrophobic effects of chemicals, other than alcohols, to various living systems or their parts are presented for comparison.

[Analysis of the correlation between hydrophilic-lipophilic balance, coefficient of diffusion and hydrogen ion concentration in a series of nonsteroidal anti-inflammatory drugs].

A thorough investigation on the dependence of rate diffusion constants (Kd) of nonsteroidal antiinflammatory drugs on pH and pKa values was carried out. It is shown that a modified multiparametric curve-fitting technique may constitute an useful tool to describe the rate diffusion pH-profiles of ionogenic substances. A comparison between the Kd values and the corresponding distribution coefficients (log D) shows that these constants identify complementary parameters very useful in the study of structure-activity relationships of ionogenic substances.

Correlation analysis in a set of X-benzyltrimethylammonium derivatives with antimuscarinic activity.

The results of a pharmacological investigation on a series of meta-substituted benzyltrimethylammonium salts possessing an antimuscarinic activity are reported. Correlative analysis shows that the pharmacodynamic activity is a function of the hydrophobic-lipophilic parameter associated with the substituent.

QSAR in a series of muscarinic agents. Note VI. Five-membered cyclic ligands.

Proceeding in our study on the muscarinic receptor site, a refinement of its topology by means of Quantitative Structure-Activity Relationships has been carried out. Specific key structures have been selected considering not only muscarine and the corresponding desether derivative, but also a set of cyclopentenyltrimethylammoniummethyl salts. These derivatives, considered in a correlation equation extended to all of the five-membered cyclic structures previously examined, significantly improve understanding of contributions of critical ligand substructures to the overall interaction.

Structure-analgesic activity relationships in a set of 2-aminobenzamide derivatives.

A set of 2-aminobenzamide derivatives designed as analgesic following the principles of correlation analysis have been prepared and tested. The analgesic effects shown by these products are similar to those of non-narcotic analgesic drugs; moreover, they do not show antipyretic effects and are inactive or very poor inhibitors of prostaglandin synthesis. Quantitative structure-activity relationships (QSAR) show that the analgesic potency (writhing test) is a function of the octanol-water partition coefficient.

Quantitative structure-activity relationships in a set of antimuscarinic agents.

Quantitative structure-activity relationships (QSAR) have been formulated for the interactions of a set of antimuscarinic agents. The antagonistic activity is found to be dependent on hydrophobic-lipophilic character and steric requirements of substituents R1 and R2 in structures of type R1R2N--CH2--CH2--+NR3R4R5. Moreover, it is shown that the incumbrance of R3, R4 and R5 groups and their polar effects on the onium ending greatly affect the antagonistic activity.

QSAR in a series of muscarinic agents. Note V. New sets of rigid and flexible ligands.

A deeper insight of muscarinic receptor attachment points is obtained on studying new sets of rigid and flexible ligands. The quantitative analysis of the correspondence between biological response and structural ligand features confirms that pD2 values are strongly dependent on hydrophobic and steric parameters. Moreover, it is shown that receptor attachment points are interrelated and their simultaneous perturbations contribute to enhance the activity with comparable effectiveness.

Synthesis, biological data and correlation analysis in a set of analgesic drugs.

A set of ortho-disubstituted benzene derivatives (2-X--C6H4NH--Y) designed as analgesics has been studied. Some physicochemical properties which are potentially correlated with the considered pharmacological activities are determined. Quantitative structure-activity relationships (QSAR) show that the analgesic potency (writhing test) is a function of the hydrophobic-lipophilic parameters associated with the structures under study.

Inhibition of butyrylcholinesterase by organophosphorus compounds: a quantitative structure-activity analysis.

Quantitative structure-activity relationships have been formulated for the interactions of a variety of inhibitors with butyrylcholinesterase. The parameters KQ, k2 and ki are found to be strongly dependent on molar refractivity as well as on the inductive effect of the leaving group --SR' in structures of the RO (X) P (O) SR' type. A model for the interaction of organophosphorus compounds is presented which gives a consistent view of the binding step, acylation and overall inhibition.

QSAR in a series of muscarinic agents. Note IV. - New pyridine and furan derivatives.

Two new series of picolyl- and furfuryltrimethylammonium salts have been prepared and studied in order to support some hypotheses previously formulated in the study of the topology of the muscarinic receptor. The general picture of ligand interactions with receptor as seen with correlation analysis is discussed. The new quantitative structure-activity relationship is compared with those previously formulated and it is shown that biological data for new congeners are well predicted by a correlation equation published earlier.

[Hydrophobic parameters in homologous series of psychopharmaceuticals].

The 1-octanol/water partition coefficients of sets of 1,4-benzodiazepine and phenothiazine derivatives are determined. The values of the hydrophobic parameters obtained by shake-flask procedure are correlated to the corresponding HPLC retention times. The existence of linear correlations between the two experimentally determined parameters clearly show that chromatographic indices model excellently the shake-flask parameters.

OSAR in a series of muscarinic agents. Note III--Alkyltrimethylammonium salts, ethers and esters of choline.

In the light of the experience gained studying various sets of muscarinic ligands related to a rigid model, flexible structures such as alkyltrimethylammonium salts, ethers and esters of choline have been prepared and their affinities (pD2) have been studied. The quantitative structure-activity relationships (QSAR) show that the pD2 value is strongly dependent on hydrophobic and steric parameters of the ligand substituent. Moreover, two indicator variables are considered to take ito account extra-activities connected with ligand special structural features.

QSAR in a series of muscarinic agents. Note II - Pyridine and furan derivatives.

Two sets of substantial picolyl and furfuryltrimethylammonium salts have been synthesized and their affinities (expressed as pD2) have been studied with the aim of characterizing muscarinic receptor spaces to which the ligand structural features bind. The new data were combined with those relative to a set of substituted benzyltrimethylammonium salts previously studied to formulate an overall QSAR which showed that the pD2 value is strongly dependent on hydrophobic and steric parameters of the ring substituent. Moreover, two indicator variables were considered to take into account the extra-activity associated with special structural features of the heterocyclic system and the further increase in activity associated with a "cooperative interaction" between the lipophilic binding of the substituent and a polar interaction of the ring heteroatom.

[Identification and dosage of psychopharmaceutical phenothiazine drugs by HPLC].

Phenothiazine neuroleptic drugs have been assayed by "Soap Chromatography", a new technique for separation of ionizable materials. The suggested procedure is applicable to a number of drugs either as pure compounds or in pharmaceutical dosage forms without prior cleanup.

[Quantitative determination of anxiolytics by high pressure liquid chromatography].

Benzodiazepine drugs have been assayed by "Soap Chromatography", a new technique for separation of ionizable materials. The suggested procedure is applicable to a number of drugs, either as pure compounds or in pharmaceutical dosage forms without prior cleanup.

[Analysis of phenothiazine neuroleptics by means of non-aqueous titrimetry].

Phenothiazine neuroleptic drugs, either as pure compounds or in pharmaceutical dosage forms have been quantitatively assayed by nonaqueous titrimetry. Suggested procedure is applicable to basic drugs and their corresponding salts without prior cleanup overcoming the interferences due to excipients.

A reanalysis of the structure-activity relationships of sulfonamide derivatives.

A reanalysis of correspondence between electronic distribution of sulfonamides and their antibacterial activity is proposed. Correlation equations show that the rate limiting steps for sulfonamide action on E. coli cell-free system and whole cell system have similar dependence on the negative logarithm of the ionization constant.