GABAB Receptor (The Receptors)

Foreword
	References
Contents
Contributors
About the Editor
Abbreviations
Part I: Molecular Biology, Biochemistry, and Functioning of the GABAB Receptor
	Chapter 1: GABAB Receptors: Molecular Organization, Function, and Alternative Drug Development by Targeting Protein-Protein Interactions
		1.1 GABAB Receptor Function
			1.1.1 Function of Pre- and Postsynaptic GABAB Receptors
				1.1.1.1 Presynaptic GABAB Receptors
				1.1.1.2 Postsynaptic GABAB Receptors
		1.2 Molecular Organization of GABAB Receptors
			1.2.1 The Extracellular Domain
			1.2.2 The Transmembrane Domain
			1.2.3 The Intracellular Domain
		1.3 Targeting Disease-Relevant GABAB Receptor Protein-Protein Interactions: A Novel Approach in GABAB Receptor Drug Discovery
			1.3.1 Targeting the Interaction of GABAB Receptors with 14-3-3ζ in Neuropathic Pain
			1.3.2 Targeting GABAB Receptor Interactions in Cerebral Ischemia
				1.3.2.1 Endoplasmic Reticulum Stress-Induced Downregulation of GABAB Receptors
				1.3.2.2 Overexcitation-Induced Downregulation of GABAB Receptors
			1.3.3 Targeting GABAB Receptor Downregulation in Psychostimulant-Induced Addiction
		1.4 Conclusions
		References
	Chapter 2: GABAB Receptor Functioning: Focus on Allosteric Modulation
		2.1 Introduction
		2.2 Structure and Mechanism of Activation of the GABAB Receptor
		2.3 Allosteric Interaction Within the GABAB Receptor and with the G Protein
		2.4 Allosteric Modulation by Positive Allosteric Modulators
		2.5 Allosteric Modulation Through Oligomerization
		2.6 Conclusion
		References
Part II: Pharmacology of Baclofen
	Chapter 3: Historical Overview on Baclofen, the Only GABAB Receptor Agonist Approved and Available for Clinical Use
		3.1 From GABA to Baclofen
		3.2 Clinical Use of Baclofen
		3.3 Baclofen Between Off-Label Use and New Indications
			3.3.1 Bronchospasm and Cough
			3.3.2 Stiff-man Syndrome
			3.3.3 Chronic Hiccup
			3.3.4 Tetanus
			3.3.5 Charcot-Marie-Tooth Disease, Type 1A
			3.3.6 Pain
			3.3.7 Trigeminal Neuralgia
			3.3.8 Migraine
			3.3.9 Cluster Headache
			3.3.10 Unstable Bladder Syndrome and Overactive Bladder
			3.3.11 Gastroesophageal Reflux Disease
			3.3.12 Fragile X Syndrome and Autism Spectrum Disorder
			3.3.13 Panic Attacks
			3.3.14 Post-Traumatic Stress Disorder
			3.3.15 Anxiety
			3.3.16 Substance Use Disorder
			3.3.17 Alcohol Use Disorder
		3.4 The Solitude of Baclofen
		3.5 Prodrug and Analogs of Baclofen
			3.5.1 Baclofen Methyl Ester
			3.5.2 Arbaclofen Placarbil
			3.5.3 Lesogaberan
			3.5.4 GHB
			3.5.5 Phenibut
		3.6 Conclusions
		References
	Chapter 4: Baclofen for the Treatment of Spasticity and Dystonia in Cerebral Palsy
		4.1 Introduction
			4.1.1 Severity of Cerebral Palsy
			4.1.2 Types of Cerebral Palsy
		4.2 Baclofen in Cerebral Palsy
			4.2.1 Mechanism of Action
			4.2.2 Oral Baclofen Treatment
			4.2.3 Intrathecal Baclofen Treatment
				4.2.3.1 Effect of Intrathecal Baclofen in Spastic Cerebral Palsy
				4.2.3.2 Effect of Intrathecal Baclofen in Dyskinetic Cerebral Palsy
		4.3 Conclusions
		References
	Chapter 5: Baclofen for the Treatment of Cough
		5.1 Introduction
		5.2 Neuronal Mechanisms Underlying Cough
		5.3 GABAB Receptor Agonism in Cough
			5.3.1 Evidence of GABAB Receptors in the Airways
		5.4 Antitussive Properties of Baclofen
		5.5 Gastroesophageal Reflux Disease-Related Cough
			5.5.1 Esophageal-Bronchial Reflex
			5.5.2 Temporal Associations Between Reflux and Cough
			5.5.3 Inhibition of Transient Lower Esophageal Sphincter Relaxations by Baclofen
				5.5.3.1 Lesogaberan
		5.6 Conclusions
		References
	Chapter 6: Baclofen for the Treatment of Alcohol Use Disorder
		6.1 Introduction
		6.2 Definitions of Alcohol Use Disorder and Alcohol Withdrawal Syndrome
		6.3 Approved Pharmacotherapies for the Treatment of Alcohol Withdrawal Syndrome and Alcohol Use Disorder
		6.4 Baclofen for the Treatment of Alcohol Withdrawal Syndrome
			6.4.1 Previous Chapter
			6.4.2 Recent RCTs
		6.5 Baclofen for Helping People with Alcohol Use Disorder to Achieve and Maintain Abstinence or Reducing Alcohol Use
			6.5.1 Previous Chapter
			6.5.2 Fixed and Low-to-Moderate Daily Doses of Baclofen
			6.5.3 Fixed and Higher Doses of Baclofen
			6.5.4 Flexible Doses of Baclofen
			6.5.5 People with Alcohol-Associated Liver Disease
			6.5.6 Systematic Reviews and Meta-Analyses
		6.6 Safety Profile
		6.7 The Unique Experience in France
		6.8 Consensus Statement on the Use of Baclofen for Alcohol Use Disorder
		6.9 Conclusions
		References
	Chapter 7: Baclofen Safety, Toxicity, Withdrawal, and Overdose
		7.1 Oral Baclofen Safety
		7.2 Baclofen Safety Concerns for Patients with Renal Impairment
		7.3 Baclofen Safety Concerns for Elderly Patients
		7.4 Baclofen Safety Concerns for Patients with Hepatic Impairment
		7.5 Intrathecal Baclofen Safety
		7.6 Baclofen Safety in Maternal-Fetal Medicine
		7.7 Baclofen Overdose and Toxicity
			7.7.1 Signs and Symptoms of Baclofen Overdose and Toxicity
			7.7.2 Treatment of Baclofen Overdose and Toxicity
		7.8 Baclofen Withdrawal
			7.8.1 Oral Baclofen Withdrawal
			7.8.2 Baclofen Withdrawal in Maternal-Fetal Medicine
			7.8.3 Intrathecal Baclofen Withdrawal
				7.8.3.1 Intrathecal Baclofen Withdrawal Imaging Evaluation
			7.8.4 Treatment of Baclofen Withdrawal
				7.8.4.1 Baclofen
				7.8.4.2 Benzodiazepines
				7.8.4.3 Cyproheptadine
				7.8.4.4 Propofol
				7.8.4.5 Dantrolene
				7.8.4.6 Dexmedetomidine
				7.8.4.7 Tizanidine
		7.9 Conclusions
		References
Part III: Chemistry and Pharmacology of Positive Allosteric Modulators
	Chapter 8: Recent Advances on the Chemistry of GABAB Receptor Allosteric Modulators
		8.1 Introduction
		8.2 Positive Allosteric Modulators Discovered in 2001–2012
		8.3 Positive Allosteric Modulators Discovered in 2013–2023
			8.3.1 Five-Membered Heterocyclic Amides
			8.3.2 Pyrimidines
			8.3.3 Condensed Ring Heterocycles
		8.4 Negative Allosteric Modulators
		8.5 Conclusions
		References
	Chapter 9: GABAB Receptor Positive Allosteric Modulators: Novel Approaches for Drug Design and Discovery
		9.1 Structure and Mechanism of the GABAB Receptor
		9.2 The GABAB Receptor as a Target in Drug Discovery
			9.2.1 Orthosteric Ligands
			9.2.2 Allosteric Ligands
		9.3 The Allosteric Binding Site as a Drug Target
		9.4 Novel Approaches for Designing Positive Allosteric Modulators
			9.4.1 Computer-Aided Methods in Structural Biology and Drug Design
				9.4.1.1 Virtual Screening
				9.4.1.2 From the Orthosteric to the Allosteric Binding Site(s)
			9.4.2 Computer-Based Simulations for Understanding GABAB Receptor Conformational Dynamics
				9.4.2.1 Molecular Dynamics and Enhanced Sampling Methods
		9.5 Conclusions
		References
	Chapter 10: Recent Advances on GABAB Receptor Positive Allosteric Modulators as Potential Pharmacotherapies for Neuropsychiatric Disorders
		10.1 Introduction
		10.2 Stress and Anxiety-Like Symptomatology
		10.3 Affective Disorders and Depression-Like Symptomatology
		10.4 Schizophrenia and Psychosis-Like Symptomatology
		10.5 Other Neuropsychiatric Disorders
			10.5.1 Anticonvulsant Activity and Epilepsy-Like Symptomatology
			10.5.2 Fragile X Syndrome
		10.6 Conclusions
		References
	Chapter 11: Recent Advances on GABAB Receptor Positive Allosteric Modulators as Potential Pharmacotherapies for Substance Use Disorder and Food Addiction
		11.1 Introduction
		11.2 GABAB Receptors and Drugs of Abuse
		11.3 Positive Allosteric Modulators of the GABAB Receptor on Behavioral Effects of Psychostimulants
		11.4 Positive Allosteric Modulators of the GABAB Receptor on Behavioral Effects of Opioids
		11.5 Positive Allosteric Modulators of the GABAB Receptor on Behavioral Effects of Nicotine
		11.6 Positive Allosteric Modulators of the GABAB Receptor on Behavioral Effects of Food
		11.7 Conclusions
		References
	Chapter 12: Recent Advances on GABAB Receptor Positive Allosteric Modulators as Potential Pharmacotherapies for Alcohol Use Disorder
		12.1 Introduction
		12.2 Overview of the Suppressing Effects of GABAB PAMs on Alcohol-Related Behaviors
			12.2.1 CGP7930
			12.2.2 GS39783
			12.2.3 BHF177
			12.2.4 rac-BHFF
			12.2.5 ADX71441
			12.2.6 CMPPE
			12.2.7 COR659
			12.2.8 ASP8062
			12.2.9 KK-92A
			12.2.10 ORM-27669
		12.3 The Putative GABAB PAM, Fendiline, and Alcohol Self-Administration
		12.4 Conclusions
		References
Part IV: Miscellanea
	Chapter 13: γ-Hydroxybutyric Acid: A GABAB/GHB Receptor Agonist with a Unique Neuropharmacological and Therapeutic Profile
		13.1 History
		13.2 Pharmacology
			13.2.1 Pharmacokinetics
			13.2.2 Pharmacodynamics
		13.3 Subjective Effects and Non-medical Use
		13.4 Functional Brain Correlates
		13.5 Sleep-Wake Cycle Regulation
		13.6 Therapeutic Use in Neurological and Musculoskeletal Disorders
		13.7 Therapeutic Use in Psychiatric Disorders
		13.8 Safety Profile and Addictive Potential
		13.9 Conclusions
		References
	Chapter 14: Naturally Occurring GABAB Receptor Ligands
		14.1 Introduction
		14.2 Overview of Medicinal Plants with GABAB Receptor-Mediated Activity
			14.2.1 Bupleurum falcatum
			14.2.2 Withania somnifera
			14.2.3 Glycyrrhiza glabra
			14.2.4 Valeriana officinalis
			14.2.5 Passiflora incarnata
			14.2.6 Hypericum perforatum
			14.2.7 Ginkgo biloba
			14.2.8 Angelica sinensis and Ligusticum chuanxiong
			14.2.9 Albizzia lebbeck
			14.2.10 Emblica officinalis
			14.2.11 Nardostachys jatamansi
			14.2.12 Clerodendrum mandarinorum
			14.2.13 Terminalia bellirica
			14.2.14 Other Medicinal Plants
		14.3 Conclusions
		References
	Chapter 15: Norman G. Bowery: A Founding Father of the GABAB Receptor Research Field: Reflections on His Contribution
		15.1 Norman Bowery
		15.2 Norman and Early Evidence of a Second Type of GABA Receptor (1970s–1982)
		15.3 Norman’s Studies on the “Novel GABA Receptor” (1982–1992)
		15.4 Norman’s Pharmacological Studies on the GABAB Receptor (1993–1997)
		15.5 When Norman Met Alessandra: Localization and Expression Studies of the GABAB Receptor in the Brain and Spinal Cord (1998–2003)
		15.6 Norman’s 2004–2008
		15.7 Conclusions
		References