The electronic properties of small molecules can be calculated quickly and with a reasonable degree of accuracy using semiempirical QM methods. In this study a set of QM properties derived from frontier electron theory have been used to produce a predictive model of the dissociation constants of phenols, benzoic acids and aliphatic carboxylic acids. The pK a values and structures of nearly 500 compounds were extracted from the Physprop database for this purpose. Multiple linear regression was used to search for relationships between pK a and the calculated QM properties. In most cases only a single independent variable, electrophilic superdelocalisability, was needed to produce a good model of pK a . The advantages of our approach are in the speed of calculation and the simplicity of the resultant models. The merits of using semiempirical methods to predict pK a are discussed in relation to previous studies.

The pK a of a compound directly influences its biopharmaceutical profile. This article describes the development of a method for estimating pK a values for a number of nitrogen containing chemical structures using semiempirical QM properties derived from frontier electron theory. Typically, the property giving the best correlation with pK a was the electrophilic superdelocalisability of the nitrogen atom resulting in regression equations with r 2 values up to 0.94. The advantages of this technique are in the simplicity of the models and the speed of calculation, suggesting that this method could be widely applied to the estimation of pK a values. The success of this approach is discussed in relation to other methods.

Schizophrenia is a debilitating mental disease affecting approximately 1% of the population worldwide. Since the discovery of the first modern treatment for schizophrenia, chlorpromazine, in 1952 there have been many new structures investigated, only a small fraction of which have resulted in clinically useful drugs. Of these, haloperidol may be regarded as the drug for first line treatment. Since then, clozapine has emerged as the benchmark therapeutic ameliorating positive and negative symptoms and devoid of movement disorders, with its greatest feature being improvement of treatment-resistant patients. However, a major, potential lethal side-effect of clozapine is the induction of agranulocytosis, a blood disorder with unknown mechanism that results in lowered white-blood cell counts and consequent susceptibility to infections. In the 50 years of antipsychotic drug development, several novel theories have evolved that focus on receptor sub-types (serotonin 5-HTsub>2A, dopamine D(2) and D(4)) and the degree to which they need to be selectively attenuated by the drugs. Also of significance is the location of these receptors in the brain in relation to the disease state, the myriad of side-effects associated with antipsychotics and physicochemical properties of antipsychotic molecules relative to models of the drugs and the GPCR receptors involved. The techniques for investigation have shown increasing sophistication and refinement over this period, involving cloned receptors and PET scanning for determination of receptor location, density and binding, and rate constants at receptors. Knowledge of receptor structure, although in its infancy since no membrane bound CNS-receptor has yet been crystallized, is likely to benefit substantially with advances in computer-aided modelling. Overall, these new techniques have resulted in a number of novel antipsychotics such as risperidone, sertindole, olanzapine, seroquel, zotepine and ziprasidone, whose design, synthesis and testing has benefited enormously from the accumulated knowledge base of the past 50 years. In this review, we will provide a comprehensive update of the theories of action and clinical profiles of the latest drugs listed. The following appraisal of the literature will provide the practising medicinal chemist interested in this critical area of research with sufficient insight and understanding, to embark on productive investigations into the design and development of new therapeutic agents devoid of clinically limiting side-effects.

On the basis of the hypothesis that there is a common structural basis for central nervous system (CNS) drug action consisting primarily of an aromatic group and a nitrogen atom, a four-point model for a common pharmacophore is defined with use of five semirigid CNS-active drug molecules: morphine, strychnine, LSD, apomorphine, and mianserin. Two of the points of the model represent possible hydrophobic interactions between the aromatic group and the receptor, while the other two represent hydrogen bonding between the nitrogen atom and the receptor. The model is then extended by the inclusion of nine additional CNS-active drug molecules: phenobarbitone, clonidine, diazepam, bicuculline, diphenylhydantoin, amphetamine, imipramine, chlorpromazine, and procyclidine, each being chosen as a key representative of a different CNS-active drug class or neurotransmitter system. Consideration of all phenyl group and nitrogen atom combinations, as well as all feasible conformations, shows that all nine molecules closely fit the common model in low-energy conformations. It is proposed that the model may eventually be used to design CNS-active drugs by mapping the relative locations of secondary binding sites. It can also be used to predict whether a given structure is likely to show CNS activity: a search over 1000 entries in the Merck Index shows a high probability of CNS activity in compounds fitting the common structural model.

As part of a research program to develop compounds with mixed dopamine D4 and serotonin 5-HT2A antagonist activity with potential for the treatment of schizophrenia, we report a family of compounds based on structural modification of the atypical antipsychotic, clozapine (2). The chemical synthesis, structural characterization and pharmacological evaluation of a series 4�-arylmethyl analogues of clozapine are described. Preliminary receptor binding data are presented, examining primarily the electronic and positional effects of substituents on the introduced arylmethyl group, and secondarily the nature of the aryl ring.

CD44 is a widely expressed integral membrane protein that acts as a receptor for hyaluronan (HA) and is proposed to be important to cell-extracellular matrix interaction. The Indian (In) blood group antigens reside on CD44, and most individuals express the Inb antigen. Homozygosity for the Ina allele occurs as a rare event and is associated with production of alloantibody to the common Inb antigen after transfusion or pregnancy. The present study demonstrates that a single point mutation (G252 --> C) causes an Arg46 --> Pro substitution, which is responsible for the Inb/Ina polymorphism. Additional mutations were found in In(a+b-) cDNA but were not necessary to the antigenic phenotype as determined in site-directed mutagenesis studies. In studies using CD44 chimeric constructs, Arg46 has previously been shown to be crucial for maintenance of HA-binding ability to a CD44 peptide. However, the present study demonstrates that the Arg46 --> Pro substitution does not reduce HA binding to the intact CD44 protein, which contains two proposed extracellular HA-binding motifs. Down-regulation of HA binding to In(a+b-) CD44 by anti-CD44 monoclonal antibody (mAb) ligands, however, was weakened, although all mAbs tested bound In(a+b-) and In(a-b+) CD44 equally well. Competitive inhibition studies using human anti-Inb also showed that some mAbs that inhibit HA binding to CD44 may do so by interacting with a domain separate from, but affecting the structure of, the Inb epitope.

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We report the synthesis of a second generation of tricyclic analogues of clozapine, investigating the length and nature of the chain between an ionizable nitrogen atom at physiological pH and the introduced aryl moiety. The chemistry, structural characterization, and pharmacological evaluation of this series of 4′-arylalkyl analogues of clozapine are described. Preliminary findings on the effects on activity of the nature and length of the linker, degree of unsaturation, and type of aryl moiety on blockade of dopamine D4 and serotonin 5-HT2A receptors are discussed and animal behavioural data for key compounds presented.