Naturally Occurring Benzodiazepines, Endozepines, and their Receptors

Implications for Benzodiazepine Therapy and Withdrawal

Robert B. Raffa, Diana Amantea, Robert B. Raffa, Diana Amantea

• Publisher: CRC Press
• Year: 2021
• Print ISBN:
  9780367409067
• eBook ISBN:
  9781000421279
• Topic: Medicina
• Subtopic: Farmacologia

Understanding and addressing the current opioid crisis requires knowledge of endogenous opioids (endorphins and enkephalins), but there is now evidence for a benzodiazepine crisis. Are there endogenous benzodiazepine-like substances—and what do they do? How do they affect antianxiety drugs and their adverse effects? Do they explain enigmatic prolonged benzodiazepine withdrawal syndrome? This book raises important questions about the clinical consequences of ignoring the existence of or understanding the potential influence of endogenous benzodiazepines on the therapeutic effect of benzodiazepines, their adverse effects, and the problems of withdrawal from them and other benzodiazepine receptor agonists.

FEATURES

• Discusses endogenous benzodiazepine-like substances—what do they do, and do they affect antianxiety drugs and their adverse effects?
• Presents information on enigmatic prolonged benzodiazepine withdrawal syndrome
• Describes the compounds acting at the BDZ binding sites, both exogenous (classical BDZ drugs and BDZ from food and plants) and endogenous (endozepines)
• Assesses the putative interactions in physiology, pathology, and pharmacology of the compounds acting at the BDZ binding sites

Dr. Raffa is Adjunct Professor at the University of Arizona College of Pharmacy and Professor Emeritus at Temple University School of Pharmacy. He has co-authored or edited several books on pharmacology and thermodynamics, is a co-editor of two journals, is a past president of the Mid-Atlantic Pharmacology Society, and is the recipient of research and teaching awards.

Dr. Amantea is Associate Professor of Pharmacology at the Department of Pharmacy, Health and Nutritional Sciences of the University of Calabria (Italy), where she is the leader of the Stroke Research Unit at the Section of Preclinical and Translational Pharmacology operating in the frame of the Italian Stroke Organization (ISO) Basic Science. She is a member of the Editorial Board and the Guest Editor of the 2016 Neuroscience section of Current Opinion in Pharmacology (Elsevier), and the founder and the editor of the CRC Press Frontiers in Neurotherapeutics series.

Section I

Introduction and Basic Principles

1 Introduction

Robert B. Raffa

Temple University School of Pharmacy (Emeritus)

University of Arizona College of Pharmacy (Adjunct)

Neumentum, Inc.

Enalare Therapeutics

Contents

Endogenous Opioids Lead the Way

Endogenous Benzodiazepines

Implications

References

Endogenous Opioids Lead the Way

The catalyst for the train-of-thought that led to endogenous benzodiazepines was the discovery of endogenous opioids. In the beginning, there was only the serendipitous recognition of the therapeutic (and other) effects produced by plant substances found in the liquid that exudes from the notched unripe capsule of the opium poppy (opos from the Greek word meaning juice). This level of knowledge sufficed for thousands of years. Then, a large advance in understanding occurred with the now famous publication by Sertürner in 1806¹ of the isolation of a major active ingredient of the opium poppy—morphine—and identification of its chemical structure (codeine was isolated a few years later). This put the drug-effect sequence on a firm molecular chemical basis. And it also raised a new question: how could a small molecule be responsible for a whole-body effect? And another question gradually arose: why do some chemical structures mimic morphine and codeine, but others do not? Specifically, why was there a strict relationship between chemical structure and function (SAR)? And more specifically, why was there a strict relationship between three-dimensional chemical structure and function? Why, for example, is one enantiomer of a racemic mixture often manyfold more potent in producing an effect than is the corresponding other enantiomer?

Then came a real surprise. Weijlard and Erikson in 1942² reported that a compound that had a structure somewhat similar to morphine and codeine (“opiates”) did not produce similar effects, but could reverse them. That is, it acted like an antagonist would at a receptor that mediated the effects of an agonist. So by extension, morphine-induced effects seemed to be mediated by a receptor—and morphine acted by binding to (have affinity for), and activating (intrinsic activity or efficacy), that receptor. Years of accumulated data, development of more advanced analytical techniques, and increasing refinement of in vivo studies pointed to the existence of not only one opioid receptor, but several (i.e., the existence of subtypes of opioid receptor). Proof came with the suggestion to use radiolabeled compounds in what is now known as “radioligand binding studies,”³ and the successful use of this technique was employed by three groups and reported almost simultaneously in 1973.^4,5,6 There were now opioid receptors. The next obvious question was, “Why are they there?” Could there be endogenous opiate-like substances that interacted with these receptors?

Then, Akil and colleagues⁷ reported that foot-shock stress to animals produced analgesia. How was this possible? The fact that an opioid receptor antagonist (naloxone) reversed the effect of foot-shock stress suggested the answer—the stress must have elicited the release of some opiate-like endogenous substance(s). This would explain the reversal by an opiate receptor antagonist. It was not long before endogenous opiate-like peptides (termed “opioids”) were identified, such as the endorphins, enkephalins, deltorphins, dynorphin, and more.^8,9,10,11,12 The demonstration that the inhibition of metabolic degradation of these endogenous substances produced opiate-like effects such as analgesia completed the circle by establishing a physiological role for the endogenous opioids.¹³

A similar story evolved for the benzodiazepines, but it followed by about 20 years later.¹⁴

Endogenous Benzodiazepines

In a like manner to the opioids, benzodiazepines were used clinically before their site of action was known. The first chemical synthesis of benzodiazepines was accomplished in the mid-1950s, and the first one to market, chlordiazepoxide (LIBRIUM), appeared in 1960.¹⁵ It was subsequently determined that the effects of benzodiazepines (and the Z-drugs) are mediated by agonist action at specific receptors (named after the extant chemical class, the benzodiazepine receptor) located on neurons.^16,17 But unlike the arrangement of the opioid receptor, the benzodiazepine receptor is part of another receptor, the GABA_A receptor complex.^18,19,20 The binding of benzodiazepine agonists allosterically modulates (enhances) the action of GABA (γ-aminobutyric acid)-induced transmembrane neuronal Cl⁻ influx, thereby increasing the transmembrane potential difference, rendering the neuron less likely to respond with an action potential in response to a stimulus. This results in an anxiolytic effect (substantiated by the opposite effect—seizure—produced by inverse benzodiazepine receptor agonists). But it was only in 1986 that benzodiazepines were isolated from the mammalian brain.²¹ The intriguing rest of the story is told in this volume and in recent comprehensive reviews.^14,22,23

Implications

GABA is the major inhibitory amino acid neurotransmitter in the brain. Too little or too great an influence by GABA disturbs the critical balance between GABA and the counterbalancing amino acid excitatory neurotransmitters (primarily glutamate and aspartate) (Figure 1.1).²⁴ Disturbance in GABA levels, or functioning, has been associated with anxiety.^25,26,27,28 Benzodiazepine therapy is predicated on the ability of benzodiazepine receptor agonists to modulate GABA action at the GABA_A receptor complex (Figure 1.2).

FIGURE 1.1 The binding of the inhibitory (I) neurotransmitter GABA to its site on the GABA_A receptor complex “opens” the chloride ion channel, promoting a greater influx of Cl⁻ ions. The greater influx of Cl⁻ ions increases the neuron’s transmembrane potential difference (hyperpolarization), which renders it less likely to reach threshold and “fire” (an action potential) in response to an excitatory (E) stimulus by a neurotransmitter such as aspartate.²⁴

FIGURE 1.2 The benzodiazepine receptor binding site on the large GABA_A receptor complex.

The magnitude of the clinical effect (e.g., anxiolytic) that is produced by the administration of a benzodiazepine is dependent on the dose administered. At the molecular level, this translates to the concentration (number) of benzodiazepine molecules at the receptor site, where molecules of benzodiazepine (B_z) drug reversibly combine with molecules of benzodiazepine receptor (R_B) to form a drug–receptor complex (B_zR_B), according to the law of mass action²⁹:

$${\text{B}}_{\text{Z}}+{\text{R}}_{\text{B}}\iff B_{\text{Z}}{\text{R}}_{\text{B}}\to \to \to \text{drug}\text{effect}.$$

This equation is a hallmark of pharmacodynamics, and is extremely helpful in understanding drug action and quantifying ...

Table of contents

• Cover
• Half Title
• Series Page
• Title Page
• Copyright Page
• Table of Contents
• Preface
• About the Editors
• Contributors
• Section I Introduction and Basic Principles
• Section II Naturally Occurring Benzodiazepines
• Section III Implications for Therapeutics
• Section IV Implications for Tolerance, Withdrawal, and Abuse
• Index