Antipsychotic drugs are psychiatric medication primarily used to manage psychosis (e.g., delusions or hallucinations), particularly in schizophrenia and bipolar disorder. First and second generations of antipshychotics tend to block receptors in the brain's dopamine pathways, but antipsychotic drugs encompass a wide range of receptor targets. The inhibition constant, Ki, at the level of membrane receptors is a major determinant of their pharmacokinetic behavior and, consequently, it can affect their antipsychotic activity. Here, predicted inhibition constants, Ki for 71 antipsychotics, already approved for clinical treatment, as well as representative new chemical structures which exhibit antipsychotic activity, were evaluated using 3D-QSAR-CoMSIA models. Significant values of the cross-validated correlation q2 (higher than 0.70) and the fitted correlation r2 (higher than 0.80) revealed that these models have reasonable power to predict the biological affinity of the 15 new risperidone and 12 new olanzapine derivatives in interactions with dopamine D2 and serotonin 5HT2A receptors; these compounds are suggested for further studies.

01 Nov 2008·NeuropharmacologyQ2 · MEDICINE

Serotonergic approaches in the development of novel antipsychotics

Q2 · MEDICINE

Review

Author: McCreary, Andrew C. ; Jones, Caitlin A.

Schizophrenia is a chronic, debilitating neuropsychological disease characterised by positive, negative, and cognitive deficits. In recent years, new pharmacological treatment strategies have been developed to treat the sequalae of schizophrenia based upon more selective receptor activity profiles in the hope that treatment efficacy can be increased without inducing the side-effect profiles seen with current available therapies. One such strategy involves the development of combined (partial) 5-HT(1A) agonists and D(2) receptor (partial) antagonists such as bifeprunox, SLV313, F15063 and SSR-181507 in an attempt to increase therapeutic efficacy of all symptom domains whilst alleviating adverse side effects. Other novel drugs including SLV310 and SLV314 combine selective serotonin reuptake inhibition (SSRI) functionality with D(2) receptor antagonism in an attempt to not only improve schizophrenic symptoms, but to also relieve other affective disorders intricately linked with the disorder. The main scope of this review will evaluate the major preclinical and clinical pharmacological findings concerning the aforementioned strategies and pharmacological agents, and compare their therapeutic potential with currently available antipsychotics; however, recent developments at other emerging serotonergic targets such as 5-HT(2C), 5-HT(6) and 5-HT(7) receptors will also be considered.

01 Apr 2008·Monatshefte für Chemie - Chemical Monthly

Quantitative structure – activity relationship studies on membrane receptors inhibition by antipsychotic drugs. Application to schizophrenia treatment

Author: Heinz Berner ; Speranta Avram ; Adina L. Milac ; Peter Wolschann

There are presented 6 new QSAR models, which are correlating antipsychotic activity (pK _i values at dopamine D1-D4 and serotonin (5-HT2C, 5-HT2A) receptors) with physicochem. parameters.A large data set of typical and atypical antipsychotics already approved for clin. treatment including as well representatives with new chem. structures which are exhibiting antipsychotic activity (tetrahydrofuran-, benzamide-, 3-aminoethyl-1-tetralones-, piperazine-, benzothiazepine- and pyrrolobenzazepine-derivatives) were incorporated within this study.The appropriate 2D and internal-3D mol. descriptors could be generated by the computational software MOE (Mol. Operating Environment).Significant q² (0.63-0.76) and r² (0.70-0.78) correlation coefficients were obtained, indicating that the established equations can be used within a wide range of binding constants (pK_i = 5 to 9.76).By use of these linear models an assembly of new aripiprazole structures could be established.Some of them are showing significantly improved antipsychotic activity in comparison with the parent compound

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Indication	Highest Phase	Country/Location	Organization	Date
Bipolar Disorder	Phase 1	-	AbbVie, Inc.	-
Bipolar Disorder	Phase 1	United States	Solvay SA	-
Bipolar Disorder	Phase 1	United States	Solvay SA	-
Bipolar Disorder	Phase 1	-	AbbVie, Inc.	-
Schizophrenia	Phase 1	European Union	Solvay SA	-
Schizophrenia	Phase 1	European Union	Solvay SA	-
Schizophrenia	Phase 1	United States	Solvay SA	-
Schizophrenia	Phase 1	-	AbbVie, Inc.	-
Schizophrenia	Phase 1	United States	Solvay SA	-
Schizophrenia	Phase 1	-	AbbVie, Inc.	-

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