Abecarnil inhibits [3H]flumazenil binding from cortical and cerebellar synaptosomal membranes with an IC50 values of 0.95 and 1.55 nM, respectively De Sarro et al (2000).View all Topics
John A. Davies, in xPharm: The Comprehensive Pharmacology Reference, 2007
9H-Pyrido[3,4-b]indole-3-carboxylic acid,4-(methoxymethyl)-6-(phenylmethoxy)-, 1-methylethyl ester; 6 benzyloxy 4methoxymethyl beta carboline 3 carboxylic acid isopropyl ester; sh 524; zk112119; 9H-Pyrido[3,4-b]indole-3-carboxylic acid, 4-(methoxymethyl)-6-(phenylmethoxy)-, 1-methylethyl ester; 6 benzyloxy 4 methoxymethyl beta carboline 3 carboxylic acid isopropyl ester; zk 112119
AbecarnilBeta-CarbolineRelated terms:Neuroactive β-Carbolines Norharman and Harman in Coffee
Susana Casal, in Coffee in Health and Disease Prevention, 201582.5 Summary Points•
Roasted coffee is the major known food source of norharman and harman.•
The levels of harman and norharman in the coffee beverages vary widely, being dependent on roast temperature, coffee species, and beverage type, among others factors.•
Coffee substitutes can also be regarded generally as norharman and harman sources.Five- and Six-membered Fused Systems with Bridgehead (Ring Junction) Heteroatoms concluded: 6-6 Bicyclic with One or Two N or Other Heteroatoms; Polycyclic; Spirocyclic
R.L. Riggs, D.M. Smith, in Comprehensive Heterocyclic Chemistry III, 200818.104.22.168.2(i)(a) β-Carboline derivatives
β-Carbolines (see also Section 22.214.171.124) can be prepared by a Pictet–Spengler reaction between tryptophan derivatives and aldehydes. This general reaction gives compounds such as 405, which provide the starting point for the synthesis of a range of fused pyrazinocarbolines, as shown in Scheme 94.Sign in to download full-size image
Construction of the pyrazine ring can be achieved in several ways. Acylation of the end ring nitrogen with BOC-protected glycine leads to pyrazine-fused β-carbolines 406 either by thermolysis at >200 °C <1998TA3115>, by reaction with TFA at room temperature <1998JOC2724>, or by treatment with silica under microwave irradiation <2001T4437>, a protocol which has been used for the solid-supported synthesis of a library of derivatives <1998TL1291>. Deprotection–cyclization of the 9-fluorenylmethyloxycarbonyl (Fmoc)-protected analogues is achieved by treatment with piperidine <1998TL4737, 2000JME1577, 2004SL1428>. Acylation of the β-carboline esters with halogenoacetic acid derivatives gives the halogenoacetamides 407, which can then undergo reaction with amines to give the fused products 406 <2003JME4533, 2004BMC1505, 2004SL1428, 2005EJO610>. Reaction of the solid-supported β-carboline with dicarbonyldiimidazole leads to the fused pyrazinedione 408 <2003TL2211>. Benzo-fused compounds, for example, 409, can be prepared by arylation of the β-carboline with o-fluoronitrobenzene followed by reduction <2005TL6131>.
Similarly, acylation of the dipeptide 410 with bromoacetyl chloride followed by base-induced cyclization gives the pyrazinylacetate ester 411 <2001BML1251>. Compound 410 is itself cyclized with p-toluenesulfonic acid to give the (N-alkylated indole) equivalent of 406 <200JME3518>.Alkaloids
W.A. Kukula-Koch, J. Widelski, in Pharmacognosy, 20179.9.2 β-Carboline Alkaloids
The β-carbolines constitute a group of natural and synthetic alkaloids comprising a tricyclic pyrido[3,4-b]indole ring structure (Fig. 9.6) at different levels of unsaturation (dihydro-, tetrahydro, and aromatic β-carbolines).
The pyridine nitrogen atom is characterized by a more basic character than the acidic indolic nitrogen.Sign in to download full-size image
The alkaloids are derived from Peganum harmala (Syrian rue, Zygophyllaceae), a plant used as an emmenagogue and alimentary tract medicine, which is also known to evoke hallucinations.
However, recently their antiparasitic, antitumor, and antiviral properties are of greater interest compared to their defined CNS activity.
Surprisingly, the results of clinical trials confirm the increased levels of β-carbolines in the plasma of chronic alcoholics and heroin-dependent humans. They are also reported to increase the voluntary intake of alcohol .
Even though these alkaloids are richly represented in terrestrial species (see: P. incarnata in Table 9.8), a large group of β-carbolines was isolated from marine invertebrates: tunicates, sponges, soft corals, or bryozoans .Indole Alkaloid TypeDistributionExamplesMajor Pharmacological ActivitiesPharmaceutical ApplicationsDosageAdverse EffectsErgot alkaloidsClaviceps purpurea (Fr.) Tul.—ergot fungus, Clavicipitaceae onErgotamine, ergocristine, ergotoxine, ergometrineCentral sympatholytic, peripheral α1-adrenergic blockade, smooth muscle stimulator, uterine contractor–
In gynecology to contract uterine–
in migraine-type headaches–
dehydrogenated derivatives as antihypertensive, cognitive in dementiaOnly purified alkaloids are used instead of whole plant preparations.
Secale cereale–ryePyrroloindole alkaloidsPausynistalia yohimbe (K.Schum.) Pierre ex Beille (syn. Corynanthe johimbe)–yohimbe, Rubiaceae; BarkYohimbineSympatholytic, hypotensive, libido enhancer,–
In the treatment of male impotence6 mg, 3 times dailyAllergy, hypertension (when administered with tricyclic antidepressants), arrhythmia, nausea, vomiting, hallucinations.Quinoline alkaloidsCinchona genus–quina, Rubiaceae, Barkquinine, quinidine, cinchonine, cinchonidineantipyretic, analgesic, uterine contractions inducing properties, antimalarial, astringent; quinidine: antiarrhythmic; a–
Quinine: malaria (P. falciparum), fever, common flu–
quinidine: heartbeat disorders, atrial fibrillation, malaria–
indigestionIn veterinary: for gastric complaintsNutraceutical application: quinine is an ingredient of tonic drinks (bitter agent) at doses of ca. 70 mg/LAs a bitter stomachic, for malaria and common flu—1 g per dose, 3 g per day–
single alkaloids against malaria and arrhythmia, respectively: quinine 600 mg 3 times per day,quinidine 0.8–2.0 g per daylethal dose: 2–8 g of quinineAllergic reactions;cinchonism/quinism: sweaty skin, impaired hearing, blurred vision, dizziness, nausea, vomiting, diarrhea.Contraindicated in ulcers, pregnancy.Remijia genus, Rubiaceae, Barkquinidine, cupreineAntiarrhytmicHeartbeat disordersAs for quinidineAs aboveSimple indole alkaloidsStrychnos spp. L., Loganiaceae, curare;strychnine, brucine, curareArrow poison; muscle relaxantIn veterinary medicine in mono-preparations or in combination products as bitter, digestive and nerve tonic–
to stimulate ruminal motor activity after digestive disorders in sheep, goats, and cattle2–7 days, per os;
100 g of product (i.e. 3 g strychni semen) per day for adult cattle, 12.5 g product per day for sheep and goats, 15 g per day for calves, 5 g per day for weanling sheepToxic!
First symptoms: anxiety, restlessness, vomiting, nausea; later: convulsive retraction of the corners of the mouth, twitching of the facial musculature, increased sensitivity to touch and noise, symmetric cramps inhibiting respiration, anoxia, death.
Lethal oral dose for cattle and horses: 0.5 mg/kg bw; in humans—0.5–1.0 mg/kg bw.Physostigma venenosum Balf.—Calabar bean (syn. ordeal beans),
Fabaceae, Fruitphysostigmine, serine (see: rivastigmine Table 9.7)contracting the eye pupil, reversing the effects of sedative drugs, enhances cognitionmild cognitive impairment, intoxications with tranquilizers (i.v.)physostigmine salicylate in 1 mg/mL injections in
ADrapidly hydrolyzed by cholinesterases; duration of action: 45–60 min;Renal function impairment; additive effects with cholinergic agonists;bradycardia convulsionsVinca minor—common periwinkle, Apocynaceae, herbvincamine, isovincaminecerebral and cardiovascular vasodilatory drugimpairment of cognition, stupor, cerebral hypoxia, menorrhagia, hemorrhoids, cerebral ischemia, atherosclerosis
Due to marked differences in the alkaloid content in the plant, purified alkaloids are used instead of whole plant preparationsCatharanthus roseus (L.) G.Don—rosy periwinkle (syn. Madagascar periwinkle), Apocynaceae, herbvincristine, vinblastineantineoplastic, cytostaticPurified alkaloids used in standard chemotherapy in lymphoma, testicular cancer, breast cancer, uterine cancer, Kaposi’s sarcoma.–Severe allergic reactions, blood in urine, infection, severe bleeding, pain in bones, sudden shortness of breath, constipation, headache, vomiting, stomach pain, loss of appetite.Physostigma venenosum Balf.—calabar bean, ordeal bean, Fabaceae, fruitphysostigmine, serine, calabatine, calabacinecontracting the pupil of the eye, reversing the effects of sedatives, inducing cognition (cholinesterase inhibitor—semisynthetic derivative: rivastigmine); antagonist of atropine
Cognition impairment (Alzheimer’s disease), mydriatics, poisoning with atropine–seizures, loss of control over the bladder, bowels and respiratory system
Terpenoid indole alkaloidsRauwolfia serpentina (L.) Benth. ex Kurz—rauvolfia, Apocynaceae; Rootajmaline, reserpine, rescinnamine, aricine, serpentinine, yohimbineAntiarrhythmic, antihypertensive, antimetabolic, antiovulatory, temperature decreasing propertiesMild hypertension, anxiety, psychomotor tension, Raynaud’s phenomenon; in certain neuropsychiatric disordersCNS effects are dose-related, occurring more frequently with doses exceeding 500 mcg (0.5 mg) per day.depression, tiredness, impotence, anorexia, shortness of breath, bradycardia, impotence, lack of energy; interactions with: Digitalis glycosides (induces arrhythmic incidents), barbiturates, with other sympathomimetic drugs and alcohol; promotes breast cancer from previously formed cells Acts at postganglionic sympathetic nerve endings; induces the CNS storage of catecholamines.
Oral daily dose: 50 to 200 mg as a single dose or in two divided daily dosesβ-Carboline alkaloidsPassiflora incarnata L.—passion-flower, Pasifloraceae; HerbFlavonoids: vitexin
Alkaloids –: harmane, harmol, harmaloltranquilizer,
MAO inhibitor,Irritation, mental stress, headaches, heartbeat disorders, anxiety, sleeplessness, mild depression.
Over 12 years of age
Clinical studies: hallucinogenic in humans after oral, i.v. and s.c. administration (oral dose 4 mg/kg of harmaline) Comminuted herbal substance: 1–2 g in 150 mL boiling water 1–4 times daily;
Powdered herbal substance: 0.5–2 g, 1–4 times daily
Liquid alcoholic extracts:0.5–4 mL up to 4 times a day
Administration in adultsAllergy, nausea, tachycardia, vasculitis, hypertensionβ-Carboline alkaloids
Haliclona spp.Manzamine alkaloids—manzamineantileishmanial, antimalarial, antitumor, antiviral––Bleeding, fever, pain 
References Table 8: European Medicines Agency (EMA) monographs (www.ema.europa.eu); Monographs of the European Scientific Cooperative on Phytotherapy (ESCOP); European Pharmacopoeia 8.0;  Gerber JG, Freed CR, Nies AS. Antyhypertensive pharmacology. West J Med 1980; 132(5): 430–439; ; .Fused Five- and Six-membered Rings with Ring Junction Heteroatoms
Mei-Xiang Wang, in Comprehensive Heterocyclic Chemistry II, 199126.96.36.199.2.(i) Formation of one carbonheteroatom bond
β-Carboline compound (182) cyclized smoothly with the action of one equivalent of sodium carbonate to give tetrahydroindolo[2,3-a]quinolizinium bromide in 72% yield 〈52JCS650〉. Lactam (185) was produced in excellent yield from the cyclocondensation of (184) 〈72JCS(P1)731〉. These methods have been proved useful for the preparation of other indolo[2,3-a]quinolizine derivatives 〈65RTC1183, 66JHC101, 66RTC744〉.Sign in to download full-size imageSign in to download full-size image
In some convenient and efficient syntheses reported, annelation of the terminal six-membered ring with the formation of CN bond was involved 〈60AC(R)75, 68JHC799, 73OPP55, 84AJC367〉. One example demonstrated in Scheme 33, is the synthesis of indolo[2,3-a]quinolizidine (131) which has been obtained in 74% overall yield from amide (186) 〈75CPB304〉.Sign in to download full-size imageThe ionotropic GABAA receptor
Constance Hammond, in Cellular and Molecular Neurophysiology (Fourth Edition), 20159.4.3 β-carbolines reversibly decrease total GABAA current; they bind at the benzodiazepine site and are inverse agonists of the GABAA receptor
They bind to the benzodiazepine receptor site but have reverse effects: they are called ‘benzodiazepine inverse agonists’ (Table 9.1).GABA siteBenzodiazepine siteSelective agonistsMuscimolFlunitrazepamIsoguvacineInverse agonists–β-CarbolinesCompetitive antagonistsBicuculline–Gabazine
The activity of outside-out patches of spinal cord neurons in culture is recorded in voltage clamp. When DMCM is applied with GABA, it decreases the number of GABAA receptor openings compared with what is observed with GABA alone (Figure 9.12a). DMCM (20–100 nM) reduces single openings as well as burst frequency. However, the number of openings per burst is unchanged.
The time spent by the GABAA channel in the open or bursting states is also unchanged but the time spent in the closed state is increased, consistent with a decrease in opening frequency (Figure 9.12b,c). Like diazepam, DMCM does not alter GABAA receptor single-channel conductance nor single-channel open or burst properties. DMCM decreases po and thus decreases IGABA.
Since burst frequency, but not intraburst opening frequency, is altered, it is unlikely that receptor channel opening rates (α and β) are altered by diazepam or DMCM.Abecarnil
John A. Davies, in xPharm: The Comprehensive Pharmacology Reference, 2007
Abecarnil; 9H-Pyrido[3,4-b]indole-3-carboxylic acid,4-(methoxymethyl)-6-(phenylmethoxy)-, 1-methylethyl ester; 6 benzyloxy 4methoxymethyl beta carboline 3 carboxylic acid isopropyl ester; sh 524; zk112119; 9H-Pyrido[3,4-b]indole-3-carboxylic acid, 4-(methoxymethyl)-6-(phenylmethoxy)-, 1-methylethyl ester; 6 benzyloxy 4 methoxymethyl beta carboline 3 carboxylic acid isopropyl ester; zk 112119Heterocyclic Aromatic Amines
J. Turesky, in Advances in Molecular Toxicology, 20101.2 EndogAenous formation
is a partial agonist at the benzodiazepine–GABA receptor complex, and is used in generalized anxiety disorder. Its pharmacology suggests that it may be less likely to produce sedation and tolerance, but data thus far have not shown clear differences in its adverse effects from those of classical benzodiazepines, such as alprazolam, diazepam, and lorazepam. As expected, both acute adverse effects and tolerance are dose-related.
In a multicenter, double-blind trial, abecarnil (mean daily dose 12 mg), diazepam (mean daily dose 22 mg), or placebo were given in divided doses for 6 weeks to 310 patients with generalized anxiety disorder .
Those who had improved at 6 weeks could volunteer to continue double-blind treatment for a total of 24 weeks.
Slightly more patients who took diazepam (77%) and placebo (75%) completed the 6-week study than those who took abecarnil (66%). The major adverse events during abecarnil therapy were similar to those of diazepam, namely drowsiness, dizziness, fatigue, and difficulty in coordination. Abecarnil and diazepam both produced statistically significantly more symptom relief than placebo at 1 week, but at 6 weeks only diazepam was superior to placebo.
In contrast to diazepam, abecarnil did not cause withdrawal symptoms. The absence of a placebo control makes it difficult to interpret the results of another study of the use of abecarnil and diazepam in alcohol withdrawal, which appeared to show comparable efficacy and adverse effects of the two drugs .PHARMACEUTICALS | Crystallization
W. Beckmann, U. Budde, in Encyclopedia of Separation Science, 2000Habit
The external appearance of crystals is called habit. The crystal habit can be influenced by the growth conditions. For example, crystals of the A modification of Abecarnil, a β-carboline derivative, grown after spontaneous nucleation at high supersaturations exhibit an avicular habit, while those grown at moderate supersaturations after seeding are still needle like but thicker and more rod-like (Figure 5).Sign in to download full-size image
Other factors determining the crystal habit are the solvent and the impurity profile of the material to be crystallized. The impurity level that influences the habit – and other properties – can be as low as ppm. Figure 6 shows the habits of a steroid crystallized from two different solvents, one more protic (solvent I) and the other more aprotic (solvent II). Of course, the different habits lead to a different behaviour in downstream processing.Sign in to download full-size imageMedications for Sedative Dependence
Annemarie Heberlein, Thomas Hillemacher, in Interventions for Addiction, 2013GABAA Receptor
Recently developed substances, showing subunit selectivity at the GABAA receptor, were used in order to further investigate the coherences between GABAA subunit composition and related benzodiazepine effects: SL 65 14 98, for example, is a pyridole derivate that shows selectivity for non-α1 containing GABAA receptors and potentates GABA effects fully at GABAA α2 receptors and with lower efficacy at GABAA α3 receptors. At α1 and α5 receptors, SL 65 14 98 shows only partial agonism as determined by measuring the modulation of GABA-mediated CL-flux in vitro.
Studies in nonhuman primates revealed that SL 65 14 98 could engender anxiolytic effects similar to diazepam, whereas muscle weakness, sedation, and ataxia, regularly seen during diazepam treatment, appeared only at doses that were much higher than those that evoked the anxiolytic effects. In drug discrimination tests, SL 65 14 98 motivated the primates as well as triazolam to work for an intravenous injection, an effect, which could be blocked by the α1 subunit antagonist beta-carboline-3-carboxylate-t-butyl ester (beta-CCT), probably because of a connectivity between reinforcing effects of benzodiazepines and their bindings properties to the α1 subunit of the GABAA receptor.
Similar to SL 65 14 98, L-838,417 shows no affinity difference in binding to GABAA receptors containing α1,2,3,5 subunits. However, it shows only potentiation of GABAergic effects at GABAA receptors that contain the α2,3,5 subunit.
At α1 containing GABAA receptors, it acts as an antagonist. Like SL 65 14 98, L-838,417 shows anxiolytic and anticonvulsant properties without motor impairments or sedative effects.
In suppressive tasks like the Vogel conflict test, L-838,417 engendered anti-conflict effects in mice without increasing unpunished drinking behavior in comparison to chlordiazepoxide or bretazanil. Moreover, SL 65 14 98 did not invoke tolerance to its anticonvulsant effects nor shows physical dependence after repeated administration.
After intermittent treatment, even a tendency to increase of effects was observed, which was denoted by a lower minimal dose required (3 instead of 10 mg kg−1 bodyweight) in order to gain anxiolytic effects in suppressive tasks.
In mice treated with L-838,417, or as well with SL 65 14 98, the inverse benzodiazepine agonist FG 7142 did not provoke clonic seizures, whereas in the same study, mice that were treated with either triazolam, clonazepam, diazepam, or alprazolam – substances that exhibit unselective affinity to GABAA receptor subunits – showed seizures regularly after a single dose of FG 7142.
Altogether a higher rate of clonic seizures under sudden withdrawal, provoked by treatment with FG-7142, was encountered in mice that had been treated with nonselective benzodiazepines, in which the possibility of seizures was descending gradually: triazolam = clonazepam = diazepam > alprazolam = midazolam = lorazepam.
Also, benzodiazepines that exhibit a subunit-specific affinity to the GABAA receptor like zolpidem – a substance which has a tenfold greater affinity to GABAA receptors that contain an α1 subunit – have been reported to show less tolerance and decreased sensitivity to seizures and likewise a reduced propensity to induce physical dependence in rodents, baboons, and humans.
Likewise abecarnil, another GABAA ligand, that binds with the highest affinity to the α1 subunit and acts as a full agonist only at α3 subunits, does not produce diazepam like tolerance and withdrawal symptoms. Although subunit selectivity is promising regarding the development of dependence, clinical evidence suggests that the non-benzodiazepine sedative hypnotics are associated with the risk of dependence, which is mostly explained by a dosage dependent loss of binding selectivity.
Below is a list of substances with specificity for certain subunits of the GABAA – receptors that have been associated with decreased risk for dependence:•
SL 65 14 98•
the non-benzodiazepines zaleplone, zolpidem, and abecarnilAnxiety Disorders☆
B. Levant, in Reference Module in Biomedical Sciences, 2014Experimental Therapies
Corticotropin releasing hormone receptor-1 (CRHR1) antagonists appear to selectively relieve anxiety in laboratory animals without depressing central nervous system function Holsboer (2001).Agent NameDiscussionMoclobemideMeclobemide, a reversible MAO-A selective inhibitor, is effective in the treatment of social phobia.BrofaromineBrofaromine, is a reversible inhibitor of MAO-A and an inhibitor of 5HT reuptake.AbecarnilAbecarnil is a benzodiazepine receptor partial agonist. Its antianxiety effects in humans remain to be demonstrated.CP154526CP154526 is a corticotropin releasing hormone-receptor 1 antagonist that reportedly displays antidepressant and antianxiety activity.DMP-696DMP-696 is a corticotropin releasing hormone-receptor 1 antagonist that reportedly reduces stress-inducing anxiety-related behavior without compromising the hypothalamic pituitary adrenal axis.CRA 1000, CRA 1001CRA 1000 and CRA 1001 are corticotropin releasing hormone-receptor 1 antagonists.
They inhibit norepinephrine secretion elicited by conditioned fear.GepironeGepirone, like buspirone, is a 5HT1A receptor partial agonist.
Data suggest it may provide some benefit in the treatment of GAD.SerazepineSerazepine is a 5HT2 receptor antagonist that has displayed some efficacy in the treatment of GAD.Therapeutic Areas I: Central Nervous System, Pain, Metabolic Syndrome, Urology, Gastrointestinal and Cardiovascular
K.R. Gogas, ... A.C. Foster, in Comprehensive Medicinal Chemistry II, 20076.04.6.2.3 Benzodiazepine site ligands with partial efficacy
The imidazobenzodiazepines bretazenil, imidazenil, and FG-8205 (Figure 10a) are high-affinity partial agonists for GABAA receptor subtypes that contain α1, α2, α3, and α5 subunits. These compounds are anxiolytic in animal models, with a greater separation between doses required for anxiolytic versus sedative effects than that observed for diazepam. Where studied, these compounds also show little evidence for tolerance to the anxiolytic effects, do not display withdrawal, and have a lower abuse potential than full BZ agonists in nonhuman primates.
Bretazenil (Figure 10a) entered clinical studies in the mid-1980s and was efficacious in GAD and panic disorder,112 with a lower abuse potential than diazepam.113 However, bretazenil was sedative, with little evidence for separation between anxiolytic and sedative effects,114 and its clinical development was discontinued.Sign in to download full-size image
The β-carboline abecarnil (Figure 10a), has high affinity for α1-, α2-, α3-, and α5-subunit-containing GABAA receptors, and has shown partial agonist activity in some, but not all, studies. Some reported pronounced anxiolytic versus sedative and muscle relaxant activity,115 while others reported marked sedation.116 Abecarnil was evaluated in the clinic and shown to be superior to placebo, equivalent to a BZ comparator although these effects were not always significant.
The compound produced drowsiness and was discontinued in the 1990s.
The pyrazolopyrimidine, ocinaplon (Figure 10a), has relatively low affinity for rat brain BZ binding sites, being a positive allosteric modulator of GABAA receptors exhibiting partial agonist activity at all subtypes, with EC50 values in the 3–10 μM range.117 In animal models, it produces anxiolytic activity equivalent to diazepam with reduced sedative and muscle relaxant effects.
Ocinaplon had efficacy in GAD patients with 2 weeks of dosing, with a side effect profile equivalent to placebo117 and is currently in phase III development, although it is currently on hold due to liver toxicity.
The pyridobenzimidazole, RWJ-51204 (Figure 10a), has low nanomolar affinity for BZ binding sites with the characteristics of a partial agonist,116 although no data are available for its actions on discrete α-subunit-containing GABAA receptors.
In mice and monkeys, RWJ-51204 showed anxiolytic effects that were separated from doses causing sedation, although in the rat, sedative and anxiolytic effects overlapped. In monkeys the anxiolytic effects of the compound showed a lower maximum compared with benzodiazepine full agonists and were similar to other partial agonist comparators. In 1999, the compound was reported to reduce CCK-4-induced panic in normal volunteers,116 but further clinical development activities have not been reported.Neuropharmacology of Benzodiazepines
David N. Stephens, Sarah L. King, in Biological Research on Addiction, 2013Agonists, Inverse Agonists, and Partial Agonists
Apart from substances from the benzodiazepine chemical class, compounds based on a number of other chemical structures bind to the benzodiazepine-binding site.
These include (but are not limited to) members of the imidazopyridine (e.g. zolpidem), cyclopyrrolone (e.g. zopiclone), pyrazolopyrimidine (e.g. zaleplon), and β-carboline (e.g. abecarnil) chemical classes, as well as several others.
Thus, the so-called benzodiazepine-binding site on GABAA receptors is confusingly not a binding site for all psychoactive benzodiazepines, but is a binding site for members of quite diverse chemical classes.
Since these compounds bind to an allosteric site on the complex, in principle compounds might exist that modulate the actions of GABA in both positive and negative directions, and this has been found to be the case.
Thus, certain compounds from several of the chemical classes bind to apparently the same binding site as diazepam, but in contrast to diazepam reduce the ability of GABA to open the channel. The first compound discovered to act in this way was β-carboline ethyl ester, but subsequently other β-carbolines were synthesized with properties similar to those of the classical benzodiazepines, while benzodiazepine derivatives were identified that acted as negative modulators of GABA’s action. Since classical benzodiazepines have been considered to act as “agonists” at these binding sites (since they facilitate the effects of the natural neurotransmitter at the complex), compounds that reduce GABA’s effects have been named “inverse agonists.” In keeping with their opposite effects to agonists on GABA’s action (they reduce GABA-induced chloride flux), such compounds in contrast to the anxiolytic, anticonvulsant, sedative, and amnestic properties of classical benzodiazepines may induce anxiety, induce convulsions, increase vigilance, and even facilitate memory.
Between the so-called full agonists and full inverse agonists, compounds exist with a range of abilities to influence GABA’s effects, usually described as the compound’s efficacy. Such compounds range from partial agonists (weakly enhance GABA’s effects) to partial inverse agonists (weakly reduce GABA’s effects), or neutral substances that while binding to the site have little or no influence on GABA’s ability to gate chloride flux; since such compounds by binding to the benzodiazepine site prevent full agonists or full inverse agonists from binding, they are effective antagonists of the classical benzodiazepines. One such compound, flumazenil, is used clinically to reverse benzodiazepine overdose.
An obvious question that arises from the discovery of a binding site on a neurotransmitter receptor is whether natural ligands exist within the brain, and interact with that binding site to modify GABA’s action. Since antagonists have essentially no physiologica
l or behavioral effect even at doses that occupy all available binding sites, it seems unlikely that an endogenous ligand exists for the benzodiazepine-binding domain (although this does not rule out endogenous substances that act at other sites on the complex and several metabolites of steroid hormones influence GABAA receptors).
From the above, it is clear that in order to estimate the likely effect of a drug acting at the binding site, one needs to know not only its affinity for the site, but also its efficacy. Furthermore, compounds with partial agonist properties can be expected to possess some properties of benzodiazepines in the whole animal, but not others.
Thus, at least in animal models, such compounds have been shown to possess anxiolytic-like effects without being sedative. Nevertheless, despite many attempts no drug with a selective action of this kind has yet been developed successfully for clinical use.