EP0697870A1 - Btp receptor modulator of the gaba a?/chloride channel complex for prolonging the duration of the gaba induced membrane current - Google Patents

Btp receptor modulator of the gaba a?/chloride channel complex for prolonging the duration of the gaba induced membrane current

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Publication number
EP0697870A1
EP0697870A1 EP94915541A EP94915541A EP0697870A1 EP 0697870 A1 EP0697870 A1 EP 0697870A1 EP 94915541 A EP94915541 A EP 94915541A EP 94915541 A EP94915541 A EP 94915541A EP 0697870 A1 EP0697870 A1 EP 0697870A1
Authority
EP
European Patent Office
Prior art keywords
gab
chloride channel
gaba
btp
die
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP94915541A
Other languages
German (de)
French (fr)
Inventor
Christopher D. SmithKline Beecham Pharm. BENHAM
Helen Jane SmithKline Beecham Pharm. MEADOWS
David Richard SmithKline Beecham Pharm. THOMAS
Martyn Derek SmithKline Beecham Pharm. WOOD
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Ltd
Original Assignee
SmithKline Beecham Ltd
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Filing date
Publication date
Application filed by SmithKline Beecham Ltd filed Critical SmithKline Beecham Ltd
Publication of EP0697870A1 publication Critical patent/EP0697870A1/en
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to the therapeutic use of compounds found to 5 modulate a novel allostenc site of the GAB A A /Chloride channel complex.
  • Benzodiazepines exhibit a wide range of pharmacological actions, including anxiolytic activity which are mediated by specific high affinity receptor sites in the central nervous system.
  • the benzodiazepine receptor is one constituent of a supra molecular complex which also contains separate, but allosterically coupled, recognition sites for 0 ⁇ -aminobutyric acid (GABA) and barbiturates.
  • GABA 0 ⁇ -aminobutyric acid
  • barbiturates The oligomeric units of the
  • GAB A A /Chloride complex form a drug and transmitter controlled chloride channel. In the presence of GABA this channel is opened causing a GAB A-induced chloride ion current.
  • GAB A-induced chloride ion current It is known that [35S]-t-butyl-bicyclophosphorothionate (TBPS) binds with high affinity to the GAB A A complex when the chloride channel is in the closed state but with 5 low affinity when in the open state.
  • Anxiolytics such as benzodiazepines and barbiturates allosterically inhibit TBPS binding and it is thought that they do this by promoting GAB A induced chloride conductance, Le. shifting the channel to the open state.
  • PCT/GB92/02046 and PCT/GB92/02298 disclose certain ⁇ -carboline and tetrahydro- benzothienopyridine derivatives having CNS activity, such as anxiolytic, anti-depressant or anticonvulsant activity or activity useful in the treatment of sleep disorders.
  • CNS activity such as anxiolytic, anti-depressant or anticonvulsant activity or activity useful in the treatment of sleep disorders.
  • the latter five applications also disclose that such compounds inhibit TBPS binding implying that 5 they modulate the GAB A A /Chloride channel in similar manner to conventional anxiolytics such as the benzodiazepines and barbiturates.
  • the present invention provides the use of a BTP receptor modulator of the GAB A A /Chloride channel complex in the manufacture of a medicament for prolonging the duration of the GAB A-induced membrane current
  • the present invention provides the use of a BTP receptor modulator of the GAB A A /Chloride channel complex excluding compounds disclosed in the above-noted patent applications in the manufacture of a medicament for the treatment and/or prophylaxis of CNS disorders such as anxiety, sleep disorders, depression or disorders treatable with anti-convulsant agents, such as epilepsy, without the side effects normally associated with the benzodiazepine or barbiturate GAB A A /Chloride channel modulators.
  • the present invention provides the use of a compound which prolongs the duration of the GAB A-induced membrane current excluding compounds disclosed in the above-noted patent applications in the manufacture of a medicament for the treatment and/or prophylaxis of CNS disorders such as anxiety, sleep disorders, depression or disorders treatable with anti-convulsant agents, such as epilepsy, without th side effects normally associated with the benzodiazepine or barbiturate GAB A A /Chloride channel modulators.
  • BTP receptor modulators of the GAB A A /Chloride channe complex which prolong the duration of the GABA-induced membrane current include :
  • a BTP receptor modulator will be administered as a pharmaceutical composition comprising the active medicament, and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition of the invention which may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, is usually adapted fo oral or parenteral administration and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, or injectable or infusable solutions or suspensions. Orally administrable compositions are generally preferred.
  • Tablets and capsules for oral administration may be in unit dose form, and may contain conventional excipients, such as binding agents, fillers, tabletting lubricants, disintegrants and acceptable wetting agents.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and, if desired, conventional flavourings or colourants.
  • fluid unit dosage forms are prepared utilising a compound of the invention or pharmaceutically acceptable salt thereof and a sterile vehicle
  • the compound depending on the vehicle and concentration used, can be either suspended dissolved in the vehicle.
  • the compound can be dissolved for injecti and filter sterilised before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as a local anaesthetic, preservatives and buffering agents a dissolved in the vehicle.
  • the composition can be frozen after filli into the vial and the water removed under vacuum.
  • Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instea of being dissolved, and sterilization cannot be accomplished by filtration.
  • the compound can be sterilised by exposure to ethylene oxide before suspension in a sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
  • the composition may contain from 0.1 % to 99% by weight, preferably from 10 to
  • suitable unit doses may be 0.05 to 1000 mg, for anxiety more suitably 0.05 to 20.0 mg, for example 0.2 to 10 mg; and such u doses may be administered more than once a day, for example two or three a day, so that t total daily dosage is in the range of about 0.01 to 100 mg/kg; and such therapy may exten for a number of weeks or months.
  • the present invention provides a method of screening a compound for use in the treatment and/or prophylaxis of CNS disorders such as anxiety, sleep disorders, depression or disorders treatable with anti-convulsant agents, such as epilepsy, without the side effects normally associated with the benzodiazepine or barbitur GAB A A /Chloride channel modulators which method comprises measuring the ability of a compound to prolong die duration of the GAB A-induced membrane current.
  • Bovine adrenomedullary chromaffin cells were isolated and cultured by die method of Peters et al. (1989) and used for electrophysiological recordings 1-2 days after plating.
  • cells were continually perfused with a solution containing (mM): NaCl 140, KC12.5, CaCl2 1.5, MgCl2 1.2, HEPES 10 and glucose 10 (pH adjusted to 7.4 with NaOH).
  • the perfiision system operates by gravity an uses large bore tubing placed directly in line with the cell. This system allows rapid solution exchange at the cell surface with exchange possible within approximately 100ms.
  • the patch pipette solution contained in mM: CsCl 140, MgCl24, HEPES 10, EGTA 10 and NaATP 2, and was adjusted to pH 7.2 with CsOH.
  • cells were held at a membrane potential of around -80mV in the 'whole-cell configuration' of the patch clamp technique (Hamill et al. 1981).
  • Currents were evoked in response to a pulse of GABA or GABA plus the test compound which is applied through the perfiision system for approximately 7 seconds.
  • Current responses were evoked at approximately one minute intervals and were stored on die computer for latter analysis.
  • the figure shows currents evoked from a cell in response to GABA (lOpM) alone and in the presence of modulating drugs.
  • Compound A, pentobarbitone and diazepam all potentiated die GAB A-induced current with Compound A having the additional effect of dramatically slowing the decay rate of the current on washout of GABA.

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The therapeutic use of compounds found to modulate a novel allosteric site of the GABAA/Chloride channel complex is described.

Description

BTP RECEPTOR MODULATOR OF THE GABA4/CHLORIDE CHANNEL COMPLEX FOR PROLONGING THE DURATION OF THE GABA INDUCED MEMBRANE CURRENT.
The present invention relates to the therapeutic use of compounds found to 5 modulate a novel allostenc site of the GAB AA/Chloride channel complex.
Benzodiazepines exhibit a wide range of pharmacological actions, including anxiolytic activity which are mediated by specific high affinity receptor sites in the central nervous system. The benzodiazepine receptor is one constituent of a supra molecular complex which also contains separate, but allosterically coupled, recognition sites for 0 α-aminobutyric acid (GABA) and barbiturates. The oligomeric units of the
GAB AA/Chloride complex form a drug and transmitter controlled chloride channel. In the presence of GABA this channel is opened causing a GAB A-induced chloride ion current. It is known that [35S]-t-butyl-bicyclophosphorothionate (TBPS) binds with high affinity to the GAB AAcomplex when the chloride channel is in the closed state but with 5 low affinity when in the open state. Anxiolytics such as benzodiazepines and barbiturates allosterically inhibit TBPS binding and it is thought that they do this by promoting GAB A induced chloride conductance, Le. shifting the channel to the open state. Thus, the effect of drugs on TBPS binding appears to parallel chloride conductance and gives a measure of drug efficacy in terms of permeability of the chloride channel. 0 EP-A-249301, EP-A-327223, EP-A-372962, WO91/17165, PCT/GB92/01487,
PCT/GB92/02046 and PCT/GB92/02298 disclose certain α-carboline and tetrahydro- benzothienopyridine derivatives having CNS activity, such as anxiolytic, anti-depressant or anticonvulsant activity or activity useful in the treatment of sleep disorders. The latter five applications also disclose that such compounds inhibit TBPS binding implying that 5 they modulate the GAB AA/Chloride channel in similar manner to conventional anxiolytics such as the benzodiazepines and barbiturates.
However these α-carboline and benzothiophene compounds appear not to bind to the benzodiazepine or barbiturate sites of the GAB AA/Chlσride channel complex, but are now believed to bind to a novel allostenc site hereinafter referred to as the BTP 0 (benzothiophene) receptor of the GAB AA/Chloride channel complex. Such compounds can thus be classified as modulators of the BTP receptor of the GAB AA/Chloride channel complex.
It has now been found that modulators of the BTP receptor of the GAB AA/Chloride channel complex result in a dramatic prolongation of the GABA- 5 induced membrane current.
This is a novel and surprising finding since conventional anxiolytics such as benzodiazepines and barbiturates increase (potentiate) the amplitude of the GAB A-induce membrane current but do not cause a significant prolongation thereof. Although conventional anxiolytics such as the benzodiazepines are efficacious they suffer from undesirable side effects such as ataxia, sedation and interaction with ethanol. It is thought that such side effects are a consequence of these compounds significantly increasing the amplitude of the GAB A-induced membrane current which has a major inhibitory effect upon the CNS .
By contrast, it is possible that compounds which greatly prolong the duration of the GAB A-induced membrane current will be selective anxiolytic agents without sufferin the side-effects typical of the benzodiazepines.
Accordingly, the present invention provides the use of a BTP receptor modulator of the GAB AA/Chloride channel complex in the manufacture of a medicament for prolonging the duration of the GAB A-induced membrane current
In another aspect the present invention provides the use of a BTP receptor modulator of the GAB AA/Chloride channel complex excluding compounds disclosed in the above-noted patent applications in the manufacture of a medicament for the treatment and/or prophylaxis of CNS disorders such as anxiety, sleep disorders, depression or disorders treatable with anti-convulsant agents, such as epilepsy, without the side effects normally associated with the benzodiazepine or barbiturate GAB AA/Chloride channel modulators.
In a further aspect the present invention provides the use of a compound which prolongs the duration of the GAB A-induced membrane current excluding compounds disclosed in the above-noted patent applications in the manufacture of a medicament for the treatment and/or prophylaxis of CNS disorders such as anxiety, sleep disorders, depression or disorders treatable with anti-convulsant agents, such as epilepsy, without th side effects normally associated with the benzodiazepine or barbiturate GAB AA/Chloride channel modulators.
Particular examples of BTP receptor modulators of the GAB AA/Chloride channe complex which prolong the duration of the GABA-induced membrane current include :
4-am o-7-hyd^oxy-2-methyl-5,6,7,8-tetrahydrobenzo[b]thieno- [2,3-b]pyridine-3- carboxylic acid, but-2-ynyl ester, 4-ammo-7,7-ethylenedioxy-2-memyl-5,6,7,8-tetrahydrobenzo[b]-tWeno[2,3-b]pyridine-3- carboxylic acid, cyclopropylmethyl ester, and
11 -amino-2,6-dimethyl- 1 ,2,3,4-tetrahydro-6H-quinindolin- 1-one, hereinafter referred to as compounds A, B and C respectively.
For therapeutic use a BTP receptor modulator will be administered as a pharmaceutical composition comprising the active medicament, and a pharmaceutically acceptable carrier. A pharmaceutical composition of the invention, which may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, is usually adapted fo oral or parenteral administration and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, or injectable or infusable solutions or suspensions. Orally administrable compositions are generally preferred.
Tablets and capsules for oral administration may be in unit dose form, and may contain conventional excipients, such as binding agents, fillers, tabletting lubricants, disintegrants and acceptable wetting agents. The tablets may be coated according to methods well known in normal pharmaceutical practice.
Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and, if desired, conventional flavourings or colourants.
For parenteral administration, fluid unit dosage forms are prepared utilising a compound of the invention or pharmaceutically acceptable salt thereof and a sterile vehicle The compound, depending on the vehicle and concentration used, can be either suspended dissolved in the vehicle. In preparing solutions, the compound can be dissolved for injecti and filter sterilised before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents a dissolved in the vehicle. To enhance the stability, the composition can be frozen after filli into the vial and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instea of being dissolved, and sterilization cannot be accomplished by filtration. The compound can be sterilised by exposure to ethylene oxide before suspension in a sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound. The composition may contain from 0.1 % to 99% by weight, preferably from 10 to
60% by weight, of the active material, depending on the method of administration.
The dose of the compound used in the treatment of CNS disorders such as anxiety sleep disorders, depression or diseases treatable with anti-convulsant agents such as epileps will vary in the usual way with the seriousness of the disorder and the disorder itself, the weight of the sufferer, and other similar factors including the activity and molecular weigh of the active material. However, as a general guide suitable unit doses may be 0.05 to 1000 mg, for anxiety more suitably 0.05 to 20.0 mg, for example 0.2 to 10 mg; and such u doses may be administered more than once a day, for example two or three a day, so that t total daily dosage is in the range of about 0.01 to 100 mg/kg; and such therapy may exten for a number of weeks or months.
In a further aspect the present invention provides a method of screening a compound for use in the treatment and/or prophylaxis of CNS disorders such as anxiety, sleep disorders, depression or disorders treatable with anti-convulsant agents, such as epilepsy, without the side effects normally associated with the benzodiazepine or barbitur GAB AA/Chloride channel modulators which method comprises measuring the ability of a compound to prolong die duration of the GAB A-induced membrane current..
Pharmacological Data 1. Receptor binding data
Displacement of ^H flunitrazepam binding data
---Η flunitrazepam binding was used to examine the interaction of compounds wit benzodiazepine binding sites according to published methods (Martin, LL. & Doble, A. (1983) J. Neurochem.40,6, 1613-1619).
Compound IC5o(pM) Ki(μM)
A >100 >50
B >100 >50
C >100 >50
These results show that the functional effects of these compounds are not due to binding to benzodiazepine receptors.
2. Electrophysiological Studies
Electrophysiological method for recording GAB A-induced currents
Bovine adrenomedullary chromaffin cells were isolated and cultured by die method of Peters et al. (1989) and used for electrophysiological recordings 1-2 days after plating. For electrophysiological recordings cells were continually perfused with a solution containing (mM): NaCl 140, KC12.5, CaCl2 1.5, MgCl2 1.2, HEPES 10 and glucose 10 (pH adjusted to 7.4 with NaOH). The perfiision system operates by gravity an uses large bore tubing placed directly in line with the cell. This system allows rapid solution exchange at the cell surface with exchange possible within approximately 100ms. The patch pipette solution contained in mM: CsCl 140, MgCl24, HEPES 10, EGTA 10 and NaATP 2, and was adjusted to pH 7.2 with CsOH. For current recordings cells were held at a membrane potential of around -80mV in the 'whole-cell configuration' of the patch clamp technique (Hamill et al. 1981). Currents were evoked in response to a pulse of GABA or GABA plus the test compound which is applied through the perfiision system for approximately 7 seconds. Current responses were evoked at approximately one minute intervals and were stored on die computer for latter analysis.
The figure shows currents evoked from a cell in response to GABA (lOpM) alone and in the presence of modulating drugs. Compound A, pentobarbitone and diazepam all potentiated die GAB A-induced current with Compound A having the additional effect of dramatically slowing the decay rate of the current on washout of GABA. For short
(milliseconds application) of GABA, which most closely mimics in vivo synaptic activity, die effect on decay rate is the predominant action of Compound A. Compounds B and C exhibit a similar prolongation of die GAB A-induced current as Compound A.
Essentially similar effects of Compound A have been observed using neurons cultured from rat cortex and cerebellum.
References
Hamill OP, Marty A, Neher E, Sakmann B & Sigworth F (1981) Improved patch-clamp techniques for high resolution current recordings from cells and cell-free membrane patches. Pflugers Arch. 391:85-100. Peters JA, Lambert JJ & Cottrell GA (1989) An electrophysiological investigation of the characteristics and function of GAB A-A receptors on bovine adrenomedullary chromaffin cells. Pflugers Arch. 415:95-103.

Claims

Claims
1. The use of a BTP receptor modulator of me GAB AA/Chloride channel complex in the manufacture of a medicament for prolonging the duration of die GAB A- induced membrane current
2. The use of a BTP receptor modulator of me GAB AA/Chloride channel complex excluding compounds disclosed in the above-noted patent applications in the manufacture of a medicament for the treatment and/or prophylaxis of CNS disorders suc as anxiety, sleep disorders, depression or disorders treatable with anti-convulsant agents, such as epilepsy, without the side effects normally associated witii the benzodiazepine or barbiturate GAB AA/Chloride channel modulators.
3. The use of a compound which prolongs the duration of die GAB A- induced membrane current excluding compounds disclosed in the above-noted patent applications in the manufacture of a medicament for the treatment and/or prophylaxis of CNS disorders such as anxiety, sleep disorders, depression or disorders treatable with anti convulsant agents, such as epilepsy, without the side effects normally associated with the benzodiazepine or barbiturate GAB AA/Chloride channel modulators.
4. A method of screening a compound for use in the treatment and/or prophylaxis of CNS disorders such as anxiety, sleep disorders, depression or disorders treatable with anti-convulsant agents, such as epilepsy, without the side effects normally associated with the benzodiazepine or barbiturate GAB AA/Chloride channel modulators which method comprises measuring the ability of a compound to prolong die duration of die GAB A-induced membrane current.
5. A BTP receptor modulator of die GABAA/Chloride channel complex identified using the screening method of claim 4 excluding compounds disclosed in die above-noted patent applications.
EP94915541A 1993-05-05 1994-04-26 Btp receptor modulator of the gaba a?/chloride channel complex for prolonging the duration of the gaba induced membrane current Withdrawn EP0697870A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB9309179 1993-05-05
GB939309179A GB9309179D0 (en) 1993-05-05 1993-05-05 New use
PCT/EP1994/001299 WO1994025027A1 (en) 1993-05-05 1994-04-26 Btp receptor modulator of the gabaa/chloride channel complex for prolonging the duration of the gaba induced membrane current

Publications (1)

Publication Number Publication Date
EP0697870A1 true EP0697870A1 (en) 1996-02-28

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JP (1) JPH08509717A (en)
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WO (1) WO1994025027A1 (en)

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DE69738396T2 (en) * 1996-05-24 2008-12-04 Smithkline Beecham Corp. USE OF GABA RECORD INHIBITORS AS AGENTS AGAINST HUSTEN

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GB8600651D0 (en) * 1986-01-11 1986-02-19 Beecham Group Plc Compounds
GB8801491D0 (en) * 1988-01-22 1988-02-24 Beecham Group Plc Novel compounds
GB8828806D0 (en) * 1988-12-09 1989-01-18 Beecham Group Plc Novel compounds
GB9010296D0 (en) * 1990-05-08 1990-06-27 Beecham Group Plc Novel compounds
GB9117459D0 (en) * 1991-08-13 1991-09-25 Smithkline Beecham Plc Novel compounds
AU2894192A (en) * 1991-11-07 1993-06-07 Smithkline Beecham Plc Cns active tetrahydrobenzothienopyridines
GB9127188D0 (en) * 1991-12-21 1992-02-19 Smithkline Beecham Plc Novel compounds

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See references of WO9425027A1 *

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