Benzodiazepine-Based Drug Discovery

Description

Benzodiazepine-Based Drug Discovery covers benzodiazepines and benzothiazepines, which constitute two pivotal classes of heterocyclic compounds widely used as core structures of medicinal drugs for the treatment of depression, epilepsy, seizures and muscle spasms. 1,4-Benzodiazepine, 1,5-benzodiazepine, and 1,5-benzothiazepine are the most studied groups of benzodiazepines and benzothiazepines because of their outstanding potential biological activities. This book offers a broad range of recent developments and detailed coverage of the synthesis and biological activities of the drugs based on benzodiazepine and benzothiazepine matrixes, and is an ideal reference guide to researchers working in organic and medicinal chemistry. The importance of these privileged pharmacophores is not limited to the treatment of psychotic disorders because minor changes in the structures can generate various biological activities. They represent a wide range of therapeutic functions such as anticonvulsant, antianxiety, anti-depressant, antiviral, anti-HIV, anti-inflammatory, anticoagulant, anti-obesity, endothelin antagonist, cholecystokinin antagonist, and vasopressin receptor antagonist activities. Half title Title Copyright Contributors Contents Preface Acknowledgment Chapter 1 An introduction to benzodiazepines and benzothiazepines 1.1 Benzodiazepines 1.2 Benzothiazepines References Chapter 2 Structural features of 1,4-benzodiazepines 2.1 Introduction 2.2 Structural variations of 1,4-benzodiazepines 2.2.1 1,4-Benzodiazepinones 2.2.2 Fused 1,4-benzodiazepines 2.3 Conformational studies of 1,4-benzodiazepines 2.3.1 Conformational status of 1,4-benzodiazepin-2-ones 2.3.2 Conformations of 1,4-benzodiazepine-2,5-diones 2.4 Polarity and charge distribution of 1,4-benzodiazepines 2.5 1,4-Benzothiazepines 2.6 Conclusion References Chapter 3 Synthesis of 1,4-benzodiazepines and 1,4-benzothiazepines 3.1 Introduction 3.2 Synthesis of 1,4-benzodiazepines 3.3 Synthesis of fused 1,4-benzodiazepines 3.4 Synthesis of 1,4-benzothiazepines 3.5 Conclusion and future directions References Chapter 4 Biological behavior of 1,4-benzodiazepines and 1,4-benzothiazepines 4.1 Introduction 4.2 Metabolism of 1,4-benzodiazepines and 1,4-benzothiazepines 4.3 GABA metabolism and GABA receptors 4.4 Mechanism of action of 1,4-benzodiazepines on GABAA receptors 4.5 Molecular effects of chronic 1,4-benzodiazepines exposure 4.5.1 Uncoupling of GABAA receptors 4.5.2 Downregulation of GABAA receptors 4.5.3 Alternations in the GABAA receptor subunit composition 4.5.4 Alternations in glutamatergic neurotransmission 4.5.5 Alternations to neurotrophins 4.5.6 Withdrawal syndrome 4.5.7 Addiction 4.6 Effect of 1,4-benzodiazepines on cholecystokinin receptors 4.6.1 1,4-benzodiazepine-derived CCK1 receptor antagonists 4.6.2 1,4-benzodiazepine-derived CCK2 receptor antagonists 4.7 Effect of 1,4-benzodiazepines on opioid receptors 4.8 Effect of 1,4-benzothiazepines on cellular receptors 4.9 Conclusion References Chapter 5 Pharmaceutical applications of 1,4-benzodiazepines 5.1 Introduction 5.2 Short-acting 1,4-benzodiazepines 5.2.1 Midazolam 5.2.2 Triazolam 5.3 Intermediate-acting 1,4-benzodiazepines 5.3.1 Estazolam 5.3.2 Lorazepam 5.3.3 Temazepam 5.3.4 Alprazolam 5.4 Long-acting 1,4-benzodiazepines 5.4.1 Clorazepate 5.4.2 Clonazepam 5.4.3 Chlordiazepoxide 5.4.4 Flurazepam 5.4.5 Diazepam 5.4.6 Quazepam References Chapter 6 Structural features of 1,5-benzodiazepines and 1,5-benzothiazepines 6.1 Introduction 6.2 Chemical properties of 1,5-benzodiazepines 6.3 Chemical properties of 1,5-benzodiazepinones 6.4 Conformational studies of 1,5-benzodiazepines and 1,5-benzodiazepinones 6.5 Chemical properties of 1,5-benzothiazepines 6.6 Conclusion References Chapter 7 Synthesis of 1,5-benzodiazepines and 1,5-benzothiazepines 7.1 Introduction 7.2 Synthesis of 1,5-benzodiazepines 7.2.1 Synthetic methods for 1,5-benzodiazepines 7.2.2 Catalytic methods for synthesis of 1,5-benzodiazepines 7.3 Synthesis of 1,5-benzothiazepines 7.3.1 Synthetic methods for 1,5-benzothiazepines 7.3.2 Catalytic methods for synthesis of 1,5-benzothiazepines 7.3.3 Enantioselective synthesis of 1,5-benzothiazepines 7.4 Future directions References Chapter 8 Biological behavior of 1,5-benzodiazepines and 1,5-benzothiazepines 8.1 Introduction 8.2 Interaction of 1,5-benzodiazepines and 1,5-benzothiazepines with cell receptors 8.2.1 GABAA receptors 8.2.2 Peripheral benzodiazepine receptors \(PBRs\) 8.2.3 Muscarinic acetylcholine receptors 8.2.4 5-Hydroxytryptamine receptors \(5-HT\) 8.2.5 Bradykinin receptors 8.2.6 Vasopressin V2 receptor \(V2R\) 8.2.7 Cholecystokinin receptors 8.3 Interaction of 1,5-benzodiazepines and 1,5-benzothiazepines with enzymes 8.3.1 Mitogen-activated protein kinases \(MAPKs\) 8.3.2 Acyl-coenzyme A: cholesterol acyltransferase \(ACAT\) 8.3.3 Reverse transcriptase \(RT\) and integrase \(IN\) 8.3.4 Nonstructural protein 5B \(NS5B\) 8.3.5 Angiotensin-converting enzyme \(ACE\) 8.3.6 Acetylcholinesterase \(AChE\) 8.4 Interaction of 1,5-benzodiazepines and 1,5-benzothiazepines with ion channels 8.4.1 Voltage-gated Ca2+ channels 8.4.2 Voltage-gated K+ channels \(Kv\) 8.5 Interaction of 1,5-benzodiazepines and 1,5-benzothiazepines with platelets 8.6 Conclusion References Chapter 9 Pharmaceutical applications of 1,5-benzodiazepines 9.1 Introduction 9.2 Clobazam 9.2.1 Background 9.2.2 Pharmacodynamics 9.2.3 Metabolism 9.2.4 Pharmacokinetics and dosage 9.2.5 Adverse effects 9.2.6 Drug-drug interactions References Chapter 10 Pharmaceutical applications of 1,5-benzothiazepines 10.1 Introduction 10.2 Diltiazem 10.2.1 Introduction 10.2.2 Pharmacodynamics 10.2.3 Metabolism 10.2.4 Pharmacokinetics and dosage 10.2.5 Adverse effects 10.2.6 Interactions 10.3 Clentiazem 10.3.1 Introduction 10.3.2 Pharmacodynamics 10.3.3 Metabolism 10.3.4 Pharmacokinetics and dosage 10.3.5 Adverse effects 10.3.6 Interactions 10.4 Thiazesim 10.4.1 Introduction 10.4.2 Pharmacodynamics 10.4.3 Metabolism 10.5 Quetiapine 10.5.1 Introduction 10.5.2 Pharmacodynamics 10.5.3 Metabolism 10.5.4 Pharmacokinetics and dosage 10.5.5 Adverse effects 10.5.6 Interactions 10.6 Clotiapine 10.6.1 Introduction 10.6.2 Pharmacodynamics 10.6.3 Metabolism 10.6.4 Pharmacokinetics and dosage 10.6.5 Adverse effects 10.6.6 Interactions References Index