Targeting dopamine D3 and serotonin 5-HT1A and 5-HT2A receptors for developing effective antipsychotics: synthesis, biological characterization, and behavioral studies.

Combination of dopamine D3 antagonism, serotonin 5-HT1A partial agonism, and antagonism at 5-HT2A leads to a novel approach to potent atypical antipsychotics. Exploitation of the original structure-activity relationships resulted in the identification of safe and effective antipsychotics devoid of extrapyramidal symptoms liability, sedation, and catalepsy. The potential atypical antipsychotic 5bb was selected for further pharmacological investigation. The distribution of c-fos positive cells in the ventral striatum confirmed the atypical antipsychotic profile of 5bb in agreement with behavioral rodent studies. 5bb administered orally demonstrated a biphasic effect on the MK801-induced hyperactivity at dose levels not able to induce sedation, catalepsy, or learning impairment in passive avoidance. In microdialysis studies, 5bb increased the dopamine efflux in the medial prefrontal cortex. Thus, 5bb represents a valuable lead for the development of atypical antipsychotics endowed with a unique pharmacological profile for addressing negative symptoms and cognitive deficits in schizophrenia.

Discovery of bishomo(hetero)arylpiperazines as novel multifunctional ligands targeting dopamine D(3) and serotonin 5-HT(1A) and 5-HT(2A) receptors.

As a continuation of our efforts to develop innovative ligands for D(3), 5-HT(1A), and 5-HT(2A) receptors with low propensity to block hERG channels, we propose a series bishetero(homo)arylpiperazines 5a-m as novel and potent multifunctional ligands characterized by low occupancy at D(2) and 5-HT(2C) receptors.

[Waist circumference as indicator of body fat and metabolic alterations in teenagers: comparison among four references]. / Circunferência da cintura como indicador de gordura corporal e alterações metabólicas em adolescentes: comparação entre quatro referências.

OBJECTIVE: Assess diagnostic validity of four reference tables for waist circumference in female teenagers in order to detect lipid alterations, hyperinsulin, elevated homeostasis model assessment (HOMA), hyperleptinemia and excess of body adiposity. METHODS: A total of 133 female subjects, ranging from 14 to 19 years of age , were evaluated. All adolescents were recruited from public schools in Viçosa/MG. Blood samples were collected for determination of fasting plasma cholesterol total, LDL, HDL, triglycerides, insulin and leptin. Percentage of body fat was determined through tetrapolar electrical bioimpedance. Using the smallest abdominal measure it was possible to determine waist circumference and calculated values of sensibility, specificity, positive and negative predictive values. Waist circumference contingency tables were obtained using four criteria: Freedman et al., 1999; Taylor et al., 2000; McCarthy et al., 2001; and Moreno et al., 2007. RESULTS: In general, sensibility values were low for circumferences assessed and the highest values were obtained for the table of McCarthy et al., on the other hand, specificity values were high considering the table of Freedman et al. The positive predictive values were more relevant for total cholesterol and body fat percentage. CONCLUSION: Cutoffs for waist circumference used by McCarthy et al. were the most appropriate for populational assessments. Freedman's et al. proposal is appropriate for clinical use since it presents higher specificity. In addition, it can substitute high costs exams, out of the professionals' reach such as insulin and leptin.

Circunferência da cintura como indicador de gordura corporal e alterações metabólicas em adolescentes: comparação entre quatro referências / Waist circumference as indicator of body fat and metabolic alterations in teenagers: comparison among four references

OBJETIVO: Avaliar a validade diagnóstica de quatro tabelas de referência para circunferência da cintura em adolescentes do sexo feminino para detecção de alterações lipídicas, hiperinsulinemia, homeostasis model assessment (HOMA) elevado, hiperleptinemia e elevada adiposidade corporal. MÉTODOS: Avaliadas 113 adolescentes com idade entre 14 e 19 anos, provenientes de escolas públicas de Viçosa (MG). Em amostras de sangue foram dosados colesterol total, LDL, HDL, triglicerídeos, insulina e leptina. Determinado percentual de gordura corporal através de bioimpedância elétrica tetrapolar. Pela medida de menor diâmetro abdominal foi determinada a circunferência da cintura do abdômen e calculados valores de sensibilidade, especificidade, valor preditivo positivo e negativo. Foram elaboradas tabelas de contingência de classificação de circunferência da cintura em adolescentes para quatro critérios: Freedman et al., 1999; Taylor et al., 2000; McCarthy et al., 2001; e Moreno et al., 2007. RESULTADOS: Valores de sensibilidade em geral foram baixos para as referências avaliadas, sendo os maiores obtidos para a de McCarthy et al. Ao contrário, as especificidades foram altas, principalmente para a tabela de Freedman et al. Os valores preditivos positivos foram mais relevantes para colesterol total e percentual de gordura corporal. CONCLUSÃO: Os pontos de corte para circunferência da cintura de McCarthy et al. demonstraram-se os mais adequados para avaliações populacionais. A proposta de Freedman et al. por apresentar maior especificidade, é útil para uso clínico e pode substituir a realização de exames de custo elevado que em muitos locais não se encontram ao alcance dos profissionais de saúde, como leptina e insulina.

OBJECTIVE: Assess diagnostic validity of four reference tables for waist circumference in female teenagers in order to detect lipid alterations, hyperinsulin, elevated homeostasis model assessment (HOMA), hyperleptinemia and excess of body adiposity. METHODS: A total of 133 female subjects, ranging from 14 to 19 years opf age , were evaluated. All adolescents were recruited from public schools in Viçosa/MG. Blood samples were collected for determination of fasting plasma cholesterol total, LDL, HDL, triglycerides, insulin and leptin. Percentage of body fat was determined through tetrapolar electrical bioimpedance. Using the smallest abdominal measure it was possible to determine waist circumference and calculated values of sensibility, specificity, positive and negative predictive values. Waist circumference contingency tables were obtained using four criteria: Freedman et al., 1999; Taylor et al., 2000; McCarthy et al., 2001; e Moreno et al., 2007. RESULTS: In general, sensibility values were low for circumferences assessed and the highest values were obtained for the table of Mc Carthy et al., on the other hand, specificity values were high considering the table of Freedman et al. The positive predictive values were more relevant for total cholesterol and body fat percentage. CONCLUSION: Cutoffs for waist circumference used by Mc Carthy et al. were the most appropriate for populational assessments. Freedman's et al. proposal is appropriate for clinical use since it presents higher specificity. In addition, it can substitute high costs exams, out of the professionals' reach such as insulin and leptin.

Discovery of a new class of potential multifunctional atypical antipsychotic agents targeting dopamine D3 and serotonin 5-HT1A and 5-HT2A receptors: design, synthesis, and effects on behavior.

Dopamine D(3) antagonism combined with serotonin 5-HT(1A) and 5-HT(2A) receptor occupancy may represent a novel paradigm for developing innovative antipsychotics. The unique pharmacological features of 5i are a high affinity for dopamine D(3), serotonin 5-HT(1A) and 5-HT(2A) receptors, together with a low affinity for dopamine D(2) receptors (to minimize extrapyramidal side effects), serotonin 5-HT(2C) receptors (to reduce the risk of obesity under chronic treatment), and for hERG channels (to reduce incidence of torsade des pointes). Pharmacological and biochemical data, including specific c-fos expression in mesocorticolimbic areas, confirmed an atypical antipsychotic profile of 5i in vivo, characterized by the absence of catalepsy at antipsychotic dose.

An efficient approach to chiral C8/C9-piperazino-substituted 1,4-benzodiazepin-2-ones as peptidomimetic scaffolds.

A promising way to interfere with biological processes is through the modulation of protein-protein interactions by means of small molecules acting as peptidomimetics. The 1,4-benzodiazepine scaffold has been widely reported as a peptide-mimicking, pharmacogenic system. While several synthetic pathways to C6-8 substituted benzodiazepines have been disclosed, few 1,4-benzodiazepines substituted at C9 have been reported. Herein, we describe a versatile approach to introduce cyclic, protonatable functionality at C8/C9. Introduction of the piperazine system at C8 and C9 gave access to a unique functionalization of the versatile benzodiazepine skeleton, broadening tailoring options on the benzofused side of the molecule, and the possibility of discovering novel peptidomimetics potentially able to modulate protein-protein interactions. Coupling of activated amino acids with poorly reactive anilines under mild conditions, while avoiding racemization, gave easy access to these compounds. Efficient amino acid activation was obtained by exploiting the rapid formation of acid chlorides under low temperature and acid/base free conditions, using triphenylphosphine and hexachloroacetone. This procedure successfully resulted in high reaction yields, did not produce racemization (ee > 98%, as demonstrated by using chiral solvating agents), and was compatible with the acid sensitive protecting groups present in the substrates.