Sar Of Benzodiazepines

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chapter overview

Although the brain is undoubtedly the most wondrously complex organ, it is possible to distil the way it works into two opposing forces; excitation and inhibition (depressing). Central nervous system (CNS) depressants are drugs that can be used to slow down or "depress" the functions of the CNS. Although many agents have the capacity to depress the function of the CNS, CNS depressants discussed in this chapter include only anxiolytics, sedative-hypnotics, and antipsychotics.

There is some overlap between the first two groups. They often have several structural features in common and likewise often share at least one mode of action, positive modulation of the action of y-aminobutyric acid (GABA) at GABAa receptor complex. The list of anxiolytic, sedative, and hypnotic drugs is a short one—benzodiazepines, Z-drugs, barbiturates, and a miscellaneous group.

Antipsychotic drugs—previously known as neuroleptic drugs, antischizophrenic drugs, or major tranquilizers—are used in the symptomatic treatment of thought disorders (psychoses), most notably the schizophrenias. Antipsychotics are grouped into typical and atypical categories. Both categories share a common feature, a dopamine (DA)-like structure, often hydrophobically substituted. This feature can be related to the most commonly cited action of these agents, competitive antagonism of DA at D2 or occasionally D3 or D4 receptors in the limbic system. The fundamental differences between typical and atypical antipsychotics are that the atypical agents are (a) less prone to produce extrapyramidal symptoms (EPS), because they are less able to block striata D2 receptors vis-à-vis limbic D2 and D3 receptors, and (b) more active against negative symptoms (social withdrawal, apathy, anhedonia).


In addition to benzodiazepines, barbiturates, and a miscellaneous group, many drugs belonging to other pharmacological classes may possess one or more of the anxiolytic, sedative, and hypnotic activities. An arbitrary classification of these agents is as follows:

1. GABAA receptor modulators

• Benzodiazepines are highly effective anxiolytic and hypnotic agents (e.g., diazepam, chlordiazepoxide, prazepam, clorazepate, oxazepam, alprazolam, flur-

azepam, lorazepam, triazolam, temazepam, estazolam, and quazepam). They bind to benzodiazepine-binding sites on GABAa receptor (also known as benzodiazepine receptor [BzR]). They are sometimes called benzodiazepine receptor agonists (BzRAs).

• Nonbenzodiazepine hypnotics (Z-drugs): Imidazopyri-dine (zolpidem), pyrazolopyrimidine (zaleplon), and cyclopyrrolone (zopiclone and its [S]-[ + ]-enantiomer eszopiclone).

• Barbiturates including amobarbital, aprobarbital, butabarbital, pentobarbital, phenobarbital, and secobar-bital are largely obsolete and superseded by benzodi-azepines. Their use is now confined to anesthesia and treatment of epilepsy.

• General anesthetics and ethanol.

2. Melatonin-1 receptor (MTi) agonists. A new drug in this area is ramelteon (Rozerem).1 Currently, 10 Food and Drug Administration (FDA)-approved drugs for insomnia include nine BzRAs (five benzodiazepines, four non-benzodiazepines) and ramelteon.

3. Atypical azaspirodecanediones: Buspirone is a partial 5-HT1A receptor agonist and an anxiolytic. It is less sedative and has less abuse potential.

4. Miscellaneous drugs such as chloral hydrate, meprobam-ate, and glutethimide are no longer recommended, but occasionally used.

5. Antipsychotics and anticonvulsants. It has been proposed that DA has a facilitative and active role in the sleep-wakefulness cycle. Waking appears to be a state maintained by D2 receptor activation, whereas blocking D2 receptor appears to cause sedation.

6. Antidepressants: Many antidepressants cause sedation, of which trazodone, doxepin, and mirtazapine have been shown to be effective in the treatment of insomnia in patients with depression. Several selective serotonin reuptake inhibitors (SSRIs), including escitalopram, fluoxetine, flu-voxamine, paroxetine, and sertraline, became the first-line therapy for some anxiety disorders in 1990s because they are not as addictive as benzodiazepines.

7. Sedative ^-antihistamines: diphenhydramine and doxyl-amine:

Diphenhydramine is sometimes used as sleeping pills, particularly for wakeful children. It is proposed that his-tamine may have an involvement in wakefulness and rapid eye movement (REM) sleep. Histamine-related functions in the CNS are regulated at postsynaptic sites by both H1 and H2 receptors, whereas the H3 receptors appear to be a presynaptic autoreceptor regulating the synthesis and release of histamine. The Hi receptor agonists and the H3 receptor antagonists increase wakefulness, whereas the Hi receptor antagonists and H3 receptor agonists have the opposite effect. Another example of ^-antihistamines is doxylamine.

8. j-Adrenoceptor antagonists (e.g., propranolol) are sometimes used by actors and musicians to reduce the symptoms of stage fright, but their use by snooker players to minimize tremor is banned as unsportsmanlike.

9. New areas explored for sleep-promoting agents:

• Adenosine-2A receptor (A2A) agonists (adenosine is a possible endogenous sleep-producing agent).

• Linoleamide and 9,10-octadecenoamide are possible endogenous sleep-producing agents and are positive modulators of gAbAa receptors.2

• Anandamide is an endogenous cannabinoid that might be used as a lead to search for new hypnotics.

The properties and side effects of FDA-approved hypnotics and commonly used but not FDA-approved hypnotics are reviewed.3,4 Older sedative-hypnotic drugs depress the CNS in a dose-dependent manner, progressively producing calming or drowsiness (sedation), sleep, unconsciousness, surgical anesthesia, coma, and eventually death from respiratory and cardiovascular depression. Although many factors influence the pharmacokinetic profile of sedatives and hypnotics, because most of them are in the nonionized form at physiological pH, their high lipophilicity is an important factor for following properties. (a) Most of them are absorbed well from the gastrointestinal (GI) tract, with good distribution to the brain. This property is responsible for the rapid onset of CNS effects of triazolam, thiopental, and newer hypnotics. (b) Many sedative-hypnotics cross the placental barrier during pregnancy. (c) They are also detectable in breast milk. (d) Some drugs with highest lipophilicity have short duration of action because of their redistribution. (e) Most drugs in this class are highly protein bond. (f) Metabolism to more water-soluble metabolites is necessary for their clearance from the body. Thus, the primary means of elimination of the benzodiazepines is metabolism, and most of them are extensively metabolized. Consequently, their duration of action depends mainly on the rate of metabolism and if their metabolites are active. Benzodiazepines are the most important drugs in both groups; therefore, the two groups are discussed together in the first section.

GABAa Receptors, Benzodiazepines, and Related Compounds

GABA system (deficiency of GABA activity in CNS) is important in the pathophysiology of anxiety and insomnia. GABA is the most common and major inhibitory neurotrans-mitter (NT) in the brain and it exerts its rapid inhibitory action mostly through GABA receptors. It is known to activate two types of receptors, the ionotropic GABAA and GABAC receptors and the metabotropic GABAB receptor. GABAA receptor is the target for many anxiolytics and sedative-hypnotic agents including benzodiazepines, barbiturates, zolpidem, zaleplon, eszopiclone, steroids, anticonvulsive agents, and many other drugs that bind to different binding sites of the GABAA receptors in neuronal membranes in the CNS.5,6 It is a ligand-gated chloride ion channel. Upon activation, CP influx is increased and the membrane becomes hyperpolarized, resulting in neuronal inhibition.

GABAA receptor exists as heteropentomeric transmembrane subunits arranged around a central chloride ion (CP) channel. The five polypeptide subunits (each subunit has an extracellular N-terminal domain, four membrane-spanning domains, and an intracellular loop) that together make up the structure of GABAA receptors come from the subunit families a, j, y, 8, e, v, p, and f. There are six isoforms of the a-polypeptide (a1-a6), four of the j with two splice variants, and three of the y with two variants. Most receptors consist of a, j, and y combinations. Of these, a1, j2, and y2 are most common. The most common pentomeric GABA receptor combination includes two a1, two j2, and one y2 subunit. Other highly expressed combinations are a2, S2, y2 and a2, S3, y2.

The subunit composition of the receptors has great bearing on the response to benzodiazepines and other ligands. The multiplicity of subunits results in heterogeneity in GABAA receptors and is responsible, at least in part, for the pharmacological diversity in benzodiazepine effects. For example, a, j, and y subunits confer benzodiazepine sensitivity to the receptors, whereas a and j subunits confer barbiturates sensitivity to the receptors. The benzodiazepine recognition site is in the extracellular N-terminus of the a1, a2, a3, and a5 subunits. Studies suggest that a1 subunits are required for hypnotic, amnesic, and possibly anticonvulsant effects of benzodiazepines, whereas a2 subunits are required for the anxiolytic and myorelaxant effects of benzodi-azepines. The mutation to arginine of a histidine residue of the GABAA receptor a1 subunit render receptors containing that subunit insensitive to the enhancing hypnotic effects of diazepam. Whereas, if arginine replaces histidine in an a2 subunit, the anxiolytic effect of benzodiazepines is lost.5 In addition, a3 and a5 subunits may be involved in other actions of benzodiazepines; a4 or a6 subunits do not respond to benzodiazepines.

Although the binding domain of the benzodiazepines is considered to be in the N-terminal domain of the a subunit, the benzodiazepines also require a y2 subunit for most positive allosteric effects. Amino acid residues in the a1 subunit that have been identified as key binding sites within the ben-zodiazepine-binding site are His 101, Tyr 161, Thr 162, Gly 200, Ser 204, Thr 206, and Val 211. In the y subunit, Phe 77 has been identified.2,5,7-12

When benzodiazepines bind to a benzodiazepine recognition site, one of several allosteric sites that modulate the effect of GABA binding to GABAA receptors located on GABA receptor complex, the benzodiazepines induce conformational (allosteric) changes in the GABA-binding site, thereby increasing the affinity of the receptor for GABA. As a result, the frequency of CP channel openings is increased over that resulting from the binding of GABA alone, and the cell is further hyperpolarized, yielding a more pronounced decrease in cellular excitability. The benzodiazepines appear to have no direct effect on the GABAA complex or ionophore.

Several newer agents that have structural characteristics broadly related to the benzodiazepines, including imida-zopyridines (zolpidem), pyrazolopyrimidines (zaleplon), and cyclopyrrolone (eszopiclone), can act as positive modulators at the benzodiazepine a1 recognition site selectively with fewer side effects.

Benzodiazepines and related compounds can act as agonists, antagonists, or inverse agonists at the benzodiazepine-

ß-Carboline binding site on GABAa receptor. Most classical benzodiazepines are positive modulators (agonists), many probably nonselectively for all the receptor subtypes that respond to benzodiazepines. Some have been claimed to be relatively selective as T-drugs and anticonvulsants. Some jS-carbolines are negative modulators (inverse agonists) at benzodiazepine modulatory sites. Negative modulators diminish the positive effect of GABA on chloride flux. In whole animals, they appear to increase anxiety, produce panic attacks, and improve memory. There are also compounds that can occupy benzodiazepine modulatory sites, have no effect on chloride flux themselves, and block positive and negative modulators. They have been called variously antagonists, zero modulators, and neutralizing allosteric modulators. One such compound, flumazenil, is used clinically to counteract the sedative effect of benzodiazepines and benzodi-azepine overdose.

In addition to benzodiazepine allosteric modulatory sites, there are other allosteric sites that recognize respectively, barbiturates, inhalation anesthetics, alcohols, propofol (separate sites), and neurosteroids. The convulsants picrotoxin and pentylenetetrazole have definite binding sites on GABA receptors.

The field of benzodiazepines was opened with the synthesis of chlordiazepoxide by Sternbach and the discovery of its unique pharmacological properties by Randall.13 Chlordiazepoxide (see the discussion on individual compounds) is a 2-amino benzodiazepine, and other amino compounds have been synthesized. When it was discovered that

An imidazobenzodiazepinone A BZR antagonist chlordiazepoxide is rapidly metabolized to a series of active benzodiazepine-2-ones (see the general scheme of metabolic relationships), however, emphasis shifted to the synthesis and testing of the latter group. Most benzodiazepines are 5-aryl-1,4-benzodiazepines and contain a carboxam-ide group in the seven-membered diazepine ring structure. Empirical structure-activity relationships (SARs) for antianxiety activity have been tabulated for this group (analogous statements apply for the older 2-amino group).13,14 The comparative quantitative SAR on nonbenzodiazepine compounds is also reviewed.15 The following general structure helps to visualize it (Fig. 12.1).

Aromatic or heteroaromatic ring A is required for the activity that may participate in w-w stacking with aromatic amino acid residues of the receptor. An electronegative substituent at position 7 is required for activity, and the more electronegative it is, the higher the activity. Positions 6, 8, and 9 should not be substituted. A phenyl ring C at position 5 promotes activity. If this phenyl group is ortho (2') or diortho (2',6') substituted with electron-withdrawing groups, activity is increased. On the other hand, para substitution decreases activity greatly. In diazepine ring B, saturation of the 4,5-double bond or a shift of it to the 3,4-position decreases activity. Alkyl substitution at the 3-position decreases activity; substitution with a 3-hydroxyl does not. The presence or absence of the 3-hydroxyl group is important pharmacokinetically. Compounds without the 3-hydroxyl group are nonpolar, 3-hydroxylated in liver slowly to active 3-hydroxyl metabolites, and have long overall half-lives. In

Figure 12.1 • General structure and SAR of benzodiazepines.

contrast, 3-hydroxyl compounds are much more polar, rapidly converted to inactive 3-glucuronides, which are excreted in urine and thus are short-lived (Fig. 12.1). The 2-carbonyl function is important for activity, as is the nitrogen atom at position 1. The ^-alkyl side chains are tolerated. A proton-accepting group at C2 is required and may interact with histidine residue (as a proton donor) in benzodiazepine-binding site of GABAa receptor. Other triazole or imidazole rings capable of H-bonding can be fused on positions 1 and 2 and increase the activity.

Additional research yielded compounds with a fused tri-azolo ring, represented by triazolam and alprazolam. Midazolam, with a fused imidazolo ring, also followed. These compounds are short acting because they are metabolized rapidly by a-hydroxylation of the methyl substituent on the triazolo or imidazolo ring (analogs to benzylic oxidation). The resulting active a--hydroxylated metabolite is quickly inactivated by glucuronidation. The compounds are also metabolized by 3-hydroxylation of the benzodiazepine ring. Interestingly, an electron-attracting group at position 7 is not required for activity in some of these compounds.

The physicochemical and pharmacokinetic properties of the benzodiazepines greatly affect their clinical utility. Most benzodiazepines are lipophilic, in the nonionized form and thus well absorbed from the GI tract, whereas the more polar compounds (e.g., those with a 3-hydroxyl group) tend to be absorbed more slowly than the more lipophilic compounds.

These drugs tend to be highly bound to plasma proteins; in general, the more lipophilic the drug, the greater the binding. However, they do not compete with other protein-bound drugs. They are also very effectively distributed to the brain. Generally, the more lipophilic the compound, the greater is the distribution to the brain, at least initially. When diazepam is used as an anesthetic, it initially distributes to the brain and then redistributes to sites outside the brain. The benzodiazepines are extensively metabolized. The metabolism of benzodiazepines has received much study.16,17 Some of the major metabolic relationships are shown in Figure 12.2. Metabolites of some benzodiazepines are not only active but also have long half-lives, thus these drugs are long acting. Many benzodiazepines are metabo

Benzodiazepine Active Metabolites

Figure 12.2 • Metabolism of benzodiazepines and their duration of action.

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