Schizophrenia: genesis, receptorology and current therapeutics.

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.

Molecular field analysis of clozapine analogs in the development of a pharmacophore model of antipsychotic drug action.

In an attempt to elucidate some aspects of clozapine's favorable receptor binding profile, we modeled a series of 30 clozapine analogs using a pharmacophore based on the ligands octoclothepin and tefludazine. Molecular field analysis using CoMFA combined with HINT was carried out on published D2 receptor binding affinities. Several alternative alignments of the analogs gave r2 values in the range of 0.8-0.95. The final model had good predictive abilities with q2 > 0.6 and r2 > 0.9. This provides an excellent framework to aid in the design of novel antipsychotics with diminished propensity to produce clinically limiting side effects.

An NMR and theoretical study of the conformation and internal flexibility of butaclamol hydrochloride.

A theoretical (MM2) and experimental (1H and 13C NMR) study of butaclamol hydrochloride in CDCl3 has been done in order to determine preferred conformations and internal molecular flexibility of this molecule. The theoretical calculations suggest the presence of four low-energy conformations, two of which involve a trans junction of the D and E rings, with the other two involving a cis I ring junction. An alternative cis junction (cis II) was excluded on energetic grounds. The 1H NMR data strongly suggest the presence of a trans D-E ring junction and are consistent with a chair conformation of the E ring. 13C spin-lattice relaxation time measurements show that most of the molecule is rigid, although there is some degree of mobility in the seven-membered B ring, associated with rapid flipping of the bridging C8 and C9 carbons between two skewed conformations, which have previously been referred to as conformer A and conformer B (Laus et al. Heterocycles 1984, 22, 311).

NMR studies of the conformational interconversion of butaclamol in solution.

1H NMR experiments at 300 MHz have been carried out to determine the identity and study the interconversion of two conformations of butaclamol in solution. The hydrochloride salt in DMSO exists as an equilibrium mixture of two conformations, which differ in their stereochemistry about the ring junction that contains the single nitrogen atom in butaclamol. The trans form has a relative population of 80% and the cis I form 20%. In CDCl3 only the trans form is observed, while in CDCl3-DMSO mixtures, both forms are detected in a ratio (trans:cis I) that decreases as the percentage of CDCl3 decreases. For the free base in either CD2Cl2 or DMSO, only a single set of resonances is observed at room temperature, but as temperature is lowered, peaks from methine protons H4a and H13b near the ring junction broaden and (for samples in CD2Cl2) eventually split into two resonances corresponding to the cis and trans forms. It is suggested that nitrogen inversion is the dynamic process responsible for the interconversion of the two forms. Line shape analysis as a function of temperature yielded an energy barrier of 9.6 +/- 0.5 kcal/mol for the interconversion, in good agreement with values obtained from saturation transfer experiments. In the hydrochloride salt, the barrier in DMSO was somewhat higher, i.e., 17.3 +/- 0.9 kcal/mol, as determined by saturation transfer and variable-temperature measurements.

Identification of a beta-turn in the tertiary structure of a peptide fragment of the Alzheimer amyloid protein.

In an attempt to understand the three-dimensional structure of the Alzheimer amyloid protein, a fragment decapeptide was studied by nuclear magnetic resonance spectroscopy. Using two-dimensional techniques, protons close in space were identified and their interproton distances determined. These distances were then used as input data for distance geometry calculations. The resulting three-dimensional structures suggest the presence of a beta-turn in the C-terminus of the decapeptide.

A common structural model for central nervous system drugs and their receptors.

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.

The use of a temperature-profiled position transducer for the study of low-temperature growth in Gramineae : Equipment design and output interpretation.

A device is described for measuring linear extension of grass leaves during controlled cooling and heating of the growing region. The instrument was employed to investigate the sensitivity to temperature of the expanding third and fourth leaves of Lolium temulentum L. seedlings. Using a stepped temperature profile it was established that there was no lag in the response of growth rate to rapid changes in temperature below 16°C. If cooling was continued to the point where growth ceased (1°C) but no further, then rates of growth on rewarming were enhanced over the chilling range and reverted to the original rate at 20°C. Cooling to successively lower subzero temperatures before rewarming abolished the hysteretic enhancement, progressively raised the temperature at which growth resumed and decreased the rate of extension until, at-5.3°C, no recovery occurred. The temperature sensitivity of growth, measured as Q10, was essentially constant when cooling from 20°C to 5°C, with 5°C-grown leaf tissue exhibiting a higher mean Q10 than tissue developed at 20°C. The possible physiological significance of these data is discussed.

Modification by gibberellin of the growth-temperature relationship in mutant and normal genotypes of several cereals.

High-resolution growth measurements were conducted using a linear variable displacement transformer in conjunction with a temperature-programmed meristem-cooling collar. Chilling and rewarming profiles were determined for a range of Gramineae, in the presence and absence of varying concentrations of gibberellic acid (GA3). In wheat (Triticum aestivum L.) seedlings, the growth-constraining temperature (Pe) was progressively lowered by increasing GA3 concentration, with a difference of-4.8°C between controls and material treated with 10(-4) M GA3. Dwarf-5 maize (Zea mays L.) seedlings had a higher Pe than tall segregates and the difference was markedly reduced by exposure to a saturating concentration of GA3. A similar effect was observed with Tanginbozu dwarf rice (Oryza sativa L.). The growth ratetemperature responses of Rht3 gibberellin-insensitive dwarf wheat seedlings were unaffected by GA3 and the Pe values for these segregates were around 5° C higher than for normals. Slender (s1) barley (Hordeum vulgare L.) genotypes had Pe values of-7° C, compared with +4° C for wild-type material, and did not show positive hysteresis for growth rate during the rewarming phase. These studies indicate that GA3 modifies the thermal sensitivity of meristem function in Gramineae in a manner which enhances low-temperature growth.

Metabolism of methyl methacrylate: evidence for metabolism by the valine pathway of catabolism in rat and in man.

1. Evidence to support the suggestion that methyl methacrylate is metabolized by the normal pathway of valine catabolism has been obtained by the administration of methyl [Me-14C]methacrylate to rats. 2. Of the administered dose, 80% was respired as 14CO2 as predicted, and methylmalonic acid, specifically labelled with 14C in a manner consistent with the proposed pathway of metabolism, was excreted (0.22%) dose). 3. Following administration of sodium [Me-2H3]methacrylate to a human subject, [Me-2H3]methylmalonic acid was detected in the urine by g.l.c.-mass spectrometry.

Isoelectric focusing of oestradiol receptor protein from human mammary carcinoma--a comparison with dextran coated charcoal assay.

Two simple methods for the detection of specific oestradiol--17 beta protein in breast tumour tissue were investigated. Isoelectric focusing of receptor protein in polyacrylamide gel was examined as an alternative micromethod to dextran-coated charcoal receptor assay. In a series of 32 cytosols prepared from unselected breast tumour tissue, assay results agreed on the presence or absence of receptors in 97% of cases. Quantitative analysis of the positive results showed a correlation coefficient, r = 0.88. Isoelectric focusing gave significantly lower receptor concentrations than the dextran-coated charcoal method. Twenty-six Tru-Cut biopsy tumour specimens were analyzed for receptor by isoelectric focusing and the results were compared with those obtained by the dextran-coated charcoal method on the same tumour. In 88% of the specimens examined, both methods agreed as to the presence or absence of receptor protein. A correlation coefficient, r = 0.62, was calculated from the 15 positive results. There was no significant difference between the results from the two methods. Quantitative results were related to total protein concentration in the cytosol. Negative receptor status was defined as less than 5 fmol/mg cytosol protein for both methods.

The distribution of acid invertase in developing leaves of Lolium temulentum L.

The levels of invertase (E.C. 3.2.1.26) activity were measured throughout the development of the fourth leaf of Lolium temulentum. No neutral invertase activity was detected. Soluble acid invertase activity fell during leaf extension but rose again after ligule formation. This rise continued into senescence and was accompanied by the appearance of activity in the insoluble fraction. Evidence is presented that the insoluble activity was not an artefact of preparation, and that it represented an extracellular acid invertase. Fractionation of soluble invertase by gel filtration showed the appearance of a high molecular weight form at the time when insoluble activity was rising. The relationships between the different forms of the enzyme are discussed, together with their roles in leaf development.

Caring for relatives of stroke patients.

The methods used by the Rehabilitation Unit of the Repatriation General Hospital, Daw Park, to involve relatives of stroke patients in the rehabilitation process are outlined. The use of group therapy techniques for relatives is described and the issues commonly encountered are discussed. The value of the group meetings for relatives and staff is emphasized.

Toxicology of methyl methacrylate: the rate of disappearance of methyl methacrylate in human blood in vitro.

1. The rate of disappearance of methyl methacrylate in blood has been determined using an isotope dilution technique. 2. At a concentration of 10(-4) mol dm(-3), methyl methacrylate disappears with pseudo first order kinetics. 3. The half-life of methyl methacrylate in blood at 37 degrees C lies in the range 20--40 min. 4. The half-life showed no dependence on the age or sex of the blood donor. 5. A major, possibly the only, pathway of metabolism is by hydrolysis to methacrylic acid.