In silico screening of dicarboxylic acids for cocrystallization with phenylpiperazine derivatives based on both cocrystallization propensity and solubility advantage

Q4 · CHEMISTRY

Article

Author: Cysewski, Piotr

In silico screening was performed to search for binary solids in which a phenylpiperazine-derivative drug was cocrystallized with a dicarboxylic acid. The phenylpiperazine derivative could be any of 61 such drugs, while the dicarboxylic acid could be any of nine such acids. The uniqueness of this approach was that two criteria had to be fulfilled simultaneously, namely a high propensity for cocrystallization and a sufficient solubility advantage. Using the mixing enthalpies of selected pairs of crystal formers with high affinities for one another permitted the classification of candidates with a high probability of cocrystallization. Further modeling of the solubility advantage allowed the identification of many binary solids that potentially exhibit significantly enhanced solubility in water. Based on the computed values for the mixing enthalpies and solubility advantage factors, it was concluded that dicarboxylic acids are both excellent coformers for cocrystallization with phenylpiperazines and very good solubility enhancers; indeed, the use of dicarboxylic acids as coformers would allow the degree of dissolution to be tuned for many of the studied drugs. The observed similarities of the cocrystallization landscapes of the studied drugs and excipients were also explored.

01 Dec 1998·Neuroscience & Biobehavioral ReviewsQ1 · PSYCHOLOGY

An evolutionary approach to behavioral pharmacology: using drugs to understand proximate and ultimate mechanisms of different forms of aggression in mice

Q1 · PSYCHOLOGY

Review

Author: Stefano Parmigiani ; Paola Palanza ; Pier Francesco Ferrari

Psychoactive drugs (Fluprazine and Chlordiazepoxide--CDP) were used as probes to test both differences or similarities in neurochemical substrates (proximal causations) and adaptive significance (ultimate causations) of different forms of intraspecific aggression in wild mice and laboratory Swiss CD-1 counterparts. Fluprazine (1-5 mg/kg) inhibited maternal attack on female, but not on male intruders. Thus, phenotypically different attack behaviors (offence and defence respectively) which have different functions may be modulated by different neurochemical substrates. Intrasexual attack and infanticide which are phenotypically different, but share similar functions (i.e. competition for mates and resources) were equally inhibited by Fluprazine (2 mg/kg) both in males and females of wild and laboratory mice. This indicates that the neural substrates of these behaviors are related and similarly regulated in the two sexes. Fluprazine was used to test the prediction of the evolutionary model on fighting strategies in male-male asymmetric contests as far as fighting ability and resource value (mating and cohabitation with a female) are concerned. Fluprazine inhibited the intensity of fighting (i.e. more 'defensive' behavioral phenotype of attack) only in animals without previous positive fighting experience, suggesting that different behavioral strategies are based on different neurochemical modulation. Experience of attack also influenced the effects of CDP (2.5-5 mg/kg) in both lactating females and male resident mice. The reported proaggressive effects of benzodiazepines were observed only in animals with prior fighting experience in both cases. Thus the understanding of the effects of drugs on behavior demands consideration of the biological variability (e.g. genetic, previous experience and/or interindividual differences) and the adaptive significance of behavior in the experimental context. On this background ethopharmacology can be defined as an evolutionary approach to the study of a drugs effect on neurochemical mechanisms and functions of behavior.

01 Aug 1996·Physiology & BehaviorQ3 · MEDICINE

Comparing different forms of male and female aggression in wild and laboratory mice: An ethopharmacological study

Q3 · MEDICINE

Article

Author: S. Parmigiani ; R.J. Rodgers ; Pier F. Ferrari ; M. Mainardi ; P. Palanza

The purpose of this study was to compare the effects of 2 mg/kg fluprazine (a serotonergic psychoactive drug with antiaggressive properties) on intrasexual attack, infanticide, and predation (on an insect larva) in males and females of wild and Swiss mice. The results showed that, in both stocks of mice, fluprazine significantly inhibited intrasexual and infanticidal attack in both sexes, but predatory attack was not altered by the drug treatment. Motivational and neural substrates underlying intrasexual attack and infanticide appear, thus, to be related to each other, and similarly modulated in both males and females. Conversely, predatory attack seems to be under a different neurohumoral control. The similar regulation of proximal mechanisms of aggressive behavior observed in wild and Swiss mice suggests a common neurobiology of aggression. For this reason, the outbred laboratory Swiss mice appear to be a reliable model for studies on causal and functional mechanisms of aggression.

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