CA2093009A1 - Use of antagonists or partial agonists on the 5-ht 1a receptor for the treatment and prevention of cognitive disorders - Google Patents
Use of antagonists or partial agonists on the 5-ht 1a receptor for the treatment and prevention of cognitive disordersInfo
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- CA2093009A1 CA2093009A1 CA002093009A CA2093009A CA2093009A1 CA 2093009 A1 CA2093009 A1 CA 2093009A1 CA 002093009 A CA002093009 A CA 002093009A CA 2093009 A CA2093009 A CA 2093009A CA 2093009 A1 CA2093009 A1 CA 2093009A1
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- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- 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
- A61K31/445—Non condensed piperidines, e.g. piperocaine
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- 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
- A61K31/48—Ergoline derivatives, e.g. lysergic acid, ergotamine
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- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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- 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
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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Abstract
ABSTRACT OF THE DISCLOSURE
The description relates to the novel use of antagonists or partial agonists on the 5HT1a receptor to produce a medicament for the treatment and prevention of cognitive and pharmaceuticals containing these compounds.
The description relates to the novel use of antagonists or partial agonists on the 5HT1a receptor to produce a medicament for the treatment and prevention of cognitive and pharmaceuticals containing these compounds.
Description
~ q,`t,it`, Use of antagonists or partial agonists on the 5-~T1, receptor for the treatment and prevent~on of aognitive disorders The invention relates to a new use for antagonists or partial agonists on the 5-HTla receptor or their physiologically compatible salts for the production of a pharmaceutical agent for the prevention and treatment of cognitive disorders, pharmaceutical agents against cognitive disorders that contain this compound as well as the process for the production of this agent.
Serotonin (5-hydroxytryptamine, S-HT) is a neurotransmitter that is released by specific neuronal cell groups, that are in the mid brain and that innervate the entire brain. The aminergic neurotransmitter serotonin released from the neurons has modulating effects on target structures, and the effects are imparted by pharmacologically different receptors. These receptors are classified as follows: 5-HT1-like with subtypes a-e, 5-HT2, 5-HT3 and 5-HT4 receptors. Of the known 5-HT1 receptors, so far the 5HT1a subtype was tested most, since a selective agonist is available with 8-hydroxydipropylamino-tetralin (8-OH-DPAT).
It is known from EP-A-0041488 that sHTla agonists can be used in diseases that are based on a serotinin deficiency, such as senility disorders of the mental function, for example, senile dementia. Further, it is described in EP-A-0345 9~8 that 5HT1a a,~q3oo3 agonists such as 8-OH-DP~T are suitable ~or the treatment of cerebral ischemia after cardiac arrest or stroke and for the treatment of multiinfarct dementia.
By 5-HT1a agonists is meant compounds that bind to the 5-HT
receptor and trigger the biological response. 8y 5-HT1~
antagonists is meant compounds that bind to the 5-HT1~ receptor and block the biological response. By 5-HT1~ partial agonists is meant compounds that directly activate the 5-HT1a receptor but trigger a weaker max. effect.
Surprisingly it was found that antagonists or partial agonists on 5-HT1a receptors bring about an improvement of the cognitive performance.
Because of their mode of action, antagonists and partial agonists on the 5-HT1a receptor are suitable for the treatment and prevention of cognitive deficiencies that can occur in older humans or in Alzheimer's disease, in Parkinson's disease with associated cognitive impairment, in AIDS-dependent dementia and other cognitive impairments.
According to the invention partial 5-HT1a receptor agonists are suitable, that have an intrinsic activity less than that of 5-carboxamindotryptamine and 5-HT1a receptor antagonists, i.e., compounds that bind to the 5-HT1a receptor and that counteract the effect caused by agonists.
The methods for determining the 5-HT1a antagonistic or agonistic activity are described, for example, in J. Pharmacol.
Exp. Ther. 238, 248-253 (1986) and J. Pharmacol. Exp. Ther. 258, 58-65 (l99l).
~093~9 As synthetic chemical compounds that show the e~ect according to the invention there can be mentioned, for example, the following classes of partial 5-HT1a receptor agonists and 5-HT~a receptor antagonists:
1) Piperazine derivatives such as 1,2-methoxyphenyl-4-t4-2-phthalamidebutyl]-piperazine-hydrochloride (NAN-l90~, e.g., ~ydelek-Fitzgerald et al., Brain Res. 532 191-196, 1990); 2-[4-t4-(2-pyrimidinyl)-1-piperazinyl]butyl]-1,2-benzisothiozolin-3-on-l,l-dioxide (ipsapirone) (e.g. O'Connor et al., Brit. J.
Pharmacol. 101 171-177, 1990); N-t4-t4-(2-pyridinyl)-1-piperazinyl]butyl]-l,l-cyclopentanediacetamide (buspirone) (e.g., deVivo and Maayani, J. Pharmacol. Exp. Ther. 238 248-253, 1986);
8-t2-t4-(2-methoxyphenyl)-1-piperazinyl)ethyl]-8-azaspiro [4,5]-decane-7,9-dione (BMY 7378, e.g. Yocca et al., Eur. J. Pharmacol.
137 293-294, 1987); 3,3-dimethyl-1-t4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]glutarimide) (gepiron) (e.g. Eison et al., Pharmacol. Biochem. Behav. 24 701 1986) 1-[10,11-dihydro-8-(methylthio)-dibenzo[b,f]thiepin-10-yl]-4-methylpiperazine (methiothepin).
2) Benzodioxanes such as 8-(4-[(1,4-benzodioxan-2-ylmethyl)amino]butyl]-8-azaspiro[4,5]decane-7,s-dione (MDL 72832 e.g., Hibert et al., J. Med. Chem. 31 1087-1093, 1988; 8[2-[(2,3-dihydro-1,4-benzodioxin-2-yl)methylamino]ethyl]-8-azaspiro[4,5]decane-7,9-dione (MDL 73005 EF, e.g., Hibert, M. et al., Brit, J. Pharmacol. 93 Suppl. 2P, 1988; Moser, P. et al.
ibid 3P).
2~93009 3) 1,1-Diethyl-3-(8a-ergolinyl)-urea derivatives such as lisuride (e.g., the Vivi and Maayani, J. Pharmacol. Exp. Ther.
238 248-253) and terguride (e.g., Kehr, Eur. J. Pharmacol. 97, 111-119, 1984).
Serotonin (5-hydroxytryptamine, S-HT) is a neurotransmitter that is released by specific neuronal cell groups, that are in the mid brain and that innervate the entire brain. The aminergic neurotransmitter serotonin released from the neurons has modulating effects on target structures, and the effects are imparted by pharmacologically different receptors. These receptors are classified as follows: 5-HT1-like with subtypes a-e, 5-HT2, 5-HT3 and 5-HT4 receptors. Of the known 5-HT1 receptors, so far the 5HT1a subtype was tested most, since a selective agonist is available with 8-hydroxydipropylamino-tetralin (8-OH-DPAT).
It is known from EP-A-0041488 that sHTla agonists can be used in diseases that are based on a serotinin deficiency, such as senility disorders of the mental function, for example, senile dementia. Further, it is described in EP-A-0345 9~8 that 5HT1a a,~q3oo3 agonists such as 8-OH-DP~T are suitable ~or the treatment of cerebral ischemia after cardiac arrest or stroke and for the treatment of multiinfarct dementia.
By 5-HT1a agonists is meant compounds that bind to the 5-HT
receptor and trigger the biological response. 8y 5-HT1~
antagonists is meant compounds that bind to the 5-HT1~ receptor and block the biological response. By 5-HT1~ partial agonists is meant compounds that directly activate the 5-HT1a receptor but trigger a weaker max. effect.
Surprisingly it was found that antagonists or partial agonists on 5-HT1a receptors bring about an improvement of the cognitive performance.
Because of their mode of action, antagonists and partial agonists on the 5-HT1a receptor are suitable for the treatment and prevention of cognitive deficiencies that can occur in older humans or in Alzheimer's disease, in Parkinson's disease with associated cognitive impairment, in AIDS-dependent dementia and other cognitive impairments.
According to the invention partial 5-HT1a receptor agonists are suitable, that have an intrinsic activity less than that of 5-carboxamindotryptamine and 5-HT1a receptor antagonists, i.e., compounds that bind to the 5-HT1a receptor and that counteract the effect caused by agonists.
The methods for determining the 5-HT1a antagonistic or agonistic activity are described, for example, in J. Pharmacol.
Exp. Ther. 238, 248-253 (1986) and J. Pharmacol. Exp. Ther. 258, 58-65 (l99l).
~093~9 As synthetic chemical compounds that show the e~ect according to the invention there can be mentioned, for example, the following classes of partial 5-HT1a receptor agonists and 5-HT~a receptor antagonists:
1) Piperazine derivatives such as 1,2-methoxyphenyl-4-t4-2-phthalamidebutyl]-piperazine-hydrochloride (NAN-l90~, e.g., ~ydelek-Fitzgerald et al., Brain Res. 532 191-196, 1990); 2-[4-t4-(2-pyrimidinyl)-1-piperazinyl]butyl]-1,2-benzisothiozolin-3-on-l,l-dioxide (ipsapirone) (e.g. O'Connor et al., Brit. J.
Pharmacol. 101 171-177, 1990); N-t4-t4-(2-pyridinyl)-1-piperazinyl]butyl]-l,l-cyclopentanediacetamide (buspirone) (e.g., deVivo and Maayani, J. Pharmacol. Exp. Ther. 238 248-253, 1986);
8-t2-t4-(2-methoxyphenyl)-1-piperazinyl)ethyl]-8-azaspiro [4,5]-decane-7,9-dione (BMY 7378, e.g. Yocca et al., Eur. J. Pharmacol.
137 293-294, 1987); 3,3-dimethyl-1-t4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]glutarimide) (gepiron) (e.g. Eison et al., Pharmacol. Biochem. Behav. 24 701 1986) 1-[10,11-dihydro-8-(methylthio)-dibenzo[b,f]thiepin-10-yl]-4-methylpiperazine (methiothepin).
2) Benzodioxanes such as 8-(4-[(1,4-benzodioxan-2-ylmethyl)amino]butyl]-8-azaspiro[4,5]decane-7,s-dione (MDL 72832 e.g., Hibert et al., J. Med. Chem. 31 1087-1093, 1988; 8[2-[(2,3-dihydro-1,4-benzodioxin-2-yl)methylamino]ethyl]-8-azaspiro[4,5]decane-7,9-dione (MDL 73005 EF, e.g., Hibert, M. et al., Brit, J. Pharmacol. 93 Suppl. 2P, 1988; Moser, P. et al.
ibid 3P).
2~93009 3) 1,1-Diethyl-3-(8a-ergolinyl)-urea derivatives such as lisuride (e.g., the Vivi and Maayani, J. Pharmacol. Exp. Ther.
238 248-253) and terguride (e.g., Kehr, Eur. J. Pharmacol. 97, 111-119, 1984).
4) 2-Amino-tetralins such as 5-~luoro-8-hydroxy-2-(dipropylamino)-tetralin (J. Med. Chem. 1990, 33, 1541-1544) and spiperone (8-[3-(p-fluorobenzoyl)propyl]-1-phenyl-1,3,8-triazaspiro~4,5]decan-4-one).
The physiologically compatible acid addition salts of the above active ingredients as well as all possible isomers (stereoisomers and/or enantiomers) and their mixtures can be used according to the invention.
The physiologically compatible salts are derived from alkaline metals or alkaline-earth metals or the usual inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, citric acid, maleic acid or fumaric acid. The actions according to the invention are shown by the example of 1,2-methoxyphenyl-4-[4-(2-phthalamide)butyl]-piperazinehydrochloride (NAN-l90) and ipsapirone:
1. Method: "Sinqle trial passive avoidance" in rats In this test the ability of rats to remember a learned behavior after 48 hours is measured. It i~ interpreted as a measurement of long-term memory.
On the first day of the learning the animals are placed on a platform. When they jump down, they receive a short foot shocX
and are then immediately taken from the device. Two days later the animals are again placed on the same platform and the time that they remained on the platform before jumping down is measured (up to a maximum of 300 sec). The prolonged time before jumping down reflects the ability to remember the punishment experience of the first day. The test substance was administered 30 minutes before the learning phase to increase the assurance that the substance-imparted effect is attributable to the improved learning. NAN-190 is a mixed agonis.t/antagonist in different in vivo and in vitro test processes. 10 animals per group were administered 1.0; 2.0 or 4.0 mg/kg of NAN-190, dissolved in 0.85~ of NaCl, i.p. Only vehicle was administered in a control group of 10 animals.
The results show that NAN-190 (1.0 and 2.0 mg/kg i.p., administered 30 minutes before the learning phase) bring about an improved memory of the escape behavior, while 4.0 mg/kg of NAN-190 has no effect (fig. 1). In the learning phase, the treated animals show no differences in comparison with the control animals in the delay of jumping down from the platform, an indication that the treatment has not brought about any non-specific effects on performance variables.
The data was statistically analyzed by nonparametric information statistics. The number of animals that jumped down from the platform as compared with the number of animals that remained on the platform for 300 sec. (e~g., that ~howed per~ect behavior adherence) was used as a variable. This analysi~ showed an overall effect of the drug treatment (21=46, 78;
df=23;p<0.001), since more animals showed a perfect behavior adherence after treatment with 1.0 or 2.0 mg/kg of NAN-190 than after vehicle treatment. No recognizable difference resulted between the control animals and the groups treated with 4.0 mg/kg of NAN-190. The results show that the treatment with NAN-l90 of 1.0 mg/kg and 2.0 mg/kg brought about an improved learning.
2. Method: Delaved non-matchina to mosition in rats In this test the ability of rats is measured to remember a spatial arrangement. The test is interpreted as a measurement of short-term memory.
For this purpose, rats were trained in a standardized so-called "operant chambers" to remember the spatial arrangement (right or left lever of the chamber) of their last response and to react accordingly. Correct responses (matches) were rewarded by being given something to eat. The worsening of the memory caused by time can be tested by varying the time interval between presentation of the test (right or left lever). Test substances that had no specific effect on the memory influence the accuracy of the responses independently of the delay, while test substances that especially influence the working short-term memory, bring about a worsening or improvement of the performance that is directly dependent on the time delay.
In the first experiment ipsapirone HCl, dissolved in 0.85%
NaCl, was injected 30 min before the beginning of the te~t ~i.p., n-12 rats). All rats were tested with all dosages (0, 1, 3 and 10 mg/kg), the dosages were administered corresponding to a "Latin Square design". At least 2 test runs were performed without administration of test substance for separation of the test substance tests. In the second experiment the ability of ipsapirone HCl to offset an adverse effect caused by scopolamine was examined. For this purpose rats (n=12) were administered scopolamine HCl (0.14 mg/kg, dissolved in 0.85% NaCl) i.p. 45 minutes before beginning the test, followed by a 15-minute delayed administration of ipsapirone HCl (dosage and experimental performance see above).
The results of these experiments show that ipsapirone, when it is administered by itself, improves the performance in the "delayed matching" (see description) (see fig. ~). This is especially noticeable in the longer time intervals ~15 and 30 sec.). Scopolamine administration causes a drastic adverse effect on the accuracy of the responses, that is directly connected with the delay. This effect is completely counteracted by the administration of ipsapirone (3.0 mg/kg) (see fig. 3).
The data was statistically analyzed by a factorial variance analysis with the factor "delay time" and dose. In the second experiment the analysis showed a significant effect relative to the time delay since the accuracy of the correct responses 8 2~93009 decreased with time (F=104.02, df-3.33, p~0.001) and a significant effect in the dosage (F-3.96, df-3.33, p<0.001). A
post hoc analysis according to Newman Xeul showed that the rats provided significantly more frequent correct responses, if they were pretreated with 3 mg/kg of ipsapirone. In the third experiment the statistical analysis also showed a significant effect relative to the time delay, since the frequency of the correct responses decreased with time (F-55.647, df=3.33, p<0.001), a significant effect in the dosage (F=4.91, df=4.44, p<0.005) and a significant dosage: time interaction (F=2.19, df-12.132, p=0.01). A post hoc analysis showed that scopolamine has a significant adverse effect on the accuracy of responses in comparison with the control level. If the scopolamine administration was followed by an administration of ipsapirone (3 mg/kg) the test results relative to the accuracy of the responses were not significantly different from the control tests, i.e., the effect of scopolamine was completely canceled out.
These results show that ipsapirone improves the short-term memory and further can counteract the cognition-disturbing effects of scopalamine (a common, pharmacological model of the cognitive losses in the SDAT).
Based on the test results the above-described compounds bring about an improvement of cognitive functions both preventively and therapeutically analogously to hydergine and piracetam.
The invention also comprises pharmaceutical agents that contain the above-mentioned compounds in an effectit~e amount, their production and use for the treatment and prevention of the above-mentioned diseases. The pharmaceutical agents are produced according to processes known in the art, ~y the active ingredient being brought into the form of a pharmaceuttcal preparatlon, with suitable vehicle, auxiliary and/or addition substances, that is suitable for enteral or parenteral administration. The administration can take place orally or sublingually, as a solid in the form of capsules or tablets or as liquid in the form of solutions, suspensions, elixirs or emulsions or rectally in the form of suppositories or the form of injection solutions optionally also usable subcutaneously. As auxiliary agents for the desired pharmaceutical agent formulation the inert organic and inorganic vehicles known to one skilled in the art are suitable such as, for example, water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, etc. Optionally, moreover, they can contain preservatives, stabilizers, wetting agents, emulsifiers or salts to change the osmotic pressure or buffers.
The pharmaceutical preparations can be available in solid form, for example, as tablets, coated tablets, suppositories, capsules, or in liquid form, for example, as solutions, suspensions or emulsions or can be formulated as depot preparations.
As vehicle system interface-near auxiliary agents such as salts of bile acids or animal or vegetable phospholides, but also mixtures of them as well as liposomes or their components, can be used.
For oral use, tablets, coated tablets or capsules with talc and/or hydrocarbon vehicles or binders, such as, for example, lactose, corn or potato starch, are especially suitable. The use can also take place in liquid form, such as, for example, as juice, to which a sweetener is optionally added.
The dosage of the active ingredients can vary according to method of administration, age and weight of the patient, type and severity of the disease to be treated and similiar factors. The daily dose is 0.2-200 mg, and the dose can be given as a single dose administered all at once or subdivided into 2 or more daily doses. Generally the active ingredient is administered one to four times a day, optionally also together with other therapeutic active ingredients. The pharmaceutical agents according to the invention generally contain 0.01 to 20~ by weight of active ingredient relative to the preparation.
The physiologically compatible acid addition salts of the above active ingredients as well as all possible isomers (stereoisomers and/or enantiomers) and their mixtures can be used according to the invention.
The physiologically compatible salts are derived from alkaline metals or alkaline-earth metals or the usual inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, citric acid, maleic acid or fumaric acid. The actions according to the invention are shown by the example of 1,2-methoxyphenyl-4-[4-(2-phthalamide)butyl]-piperazinehydrochloride (NAN-l90) and ipsapirone:
1. Method: "Sinqle trial passive avoidance" in rats In this test the ability of rats to remember a learned behavior after 48 hours is measured. It i~ interpreted as a measurement of long-term memory.
On the first day of the learning the animals are placed on a platform. When they jump down, they receive a short foot shocX
and are then immediately taken from the device. Two days later the animals are again placed on the same platform and the time that they remained on the platform before jumping down is measured (up to a maximum of 300 sec). The prolonged time before jumping down reflects the ability to remember the punishment experience of the first day. The test substance was administered 30 minutes before the learning phase to increase the assurance that the substance-imparted effect is attributable to the improved learning. NAN-190 is a mixed agonis.t/antagonist in different in vivo and in vitro test processes. 10 animals per group were administered 1.0; 2.0 or 4.0 mg/kg of NAN-190, dissolved in 0.85~ of NaCl, i.p. Only vehicle was administered in a control group of 10 animals.
The results show that NAN-190 (1.0 and 2.0 mg/kg i.p., administered 30 minutes before the learning phase) bring about an improved memory of the escape behavior, while 4.0 mg/kg of NAN-190 has no effect (fig. 1). In the learning phase, the treated animals show no differences in comparison with the control animals in the delay of jumping down from the platform, an indication that the treatment has not brought about any non-specific effects on performance variables.
The data was statistically analyzed by nonparametric information statistics. The number of animals that jumped down from the platform as compared with the number of animals that remained on the platform for 300 sec. (e~g., that ~howed per~ect behavior adherence) was used as a variable. This analysi~ showed an overall effect of the drug treatment (21=46, 78;
df=23;p<0.001), since more animals showed a perfect behavior adherence after treatment with 1.0 or 2.0 mg/kg of NAN-190 than after vehicle treatment. No recognizable difference resulted between the control animals and the groups treated with 4.0 mg/kg of NAN-190. The results show that the treatment with NAN-l90 of 1.0 mg/kg and 2.0 mg/kg brought about an improved learning.
2. Method: Delaved non-matchina to mosition in rats In this test the ability of rats is measured to remember a spatial arrangement. The test is interpreted as a measurement of short-term memory.
For this purpose, rats were trained in a standardized so-called "operant chambers" to remember the spatial arrangement (right or left lever of the chamber) of their last response and to react accordingly. Correct responses (matches) were rewarded by being given something to eat. The worsening of the memory caused by time can be tested by varying the time interval between presentation of the test (right or left lever). Test substances that had no specific effect on the memory influence the accuracy of the responses independently of the delay, while test substances that especially influence the working short-term memory, bring about a worsening or improvement of the performance that is directly dependent on the time delay.
In the first experiment ipsapirone HCl, dissolved in 0.85%
NaCl, was injected 30 min before the beginning of the te~t ~i.p., n-12 rats). All rats were tested with all dosages (0, 1, 3 and 10 mg/kg), the dosages were administered corresponding to a "Latin Square design". At least 2 test runs were performed without administration of test substance for separation of the test substance tests. In the second experiment the ability of ipsapirone HCl to offset an adverse effect caused by scopolamine was examined. For this purpose rats (n=12) were administered scopolamine HCl (0.14 mg/kg, dissolved in 0.85% NaCl) i.p. 45 minutes before beginning the test, followed by a 15-minute delayed administration of ipsapirone HCl (dosage and experimental performance see above).
The results of these experiments show that ipsapirone, when it is administered by itself, improves the performance in the "delayed matching" (see description) (see fig. ~). This is especially noticeable in the longer time intervals ~15 and 30 sec.). Scopolamine administration causes a drastic adverse effect on the accuracy of the responses, that is directly connected with the delay. This effect is completely counteracted by the administration of ipsapirone (3.0 mg/kg) (see fig. 3).
The data was statistically analyzed by a factorial variance analysis with the factor "delay time" and dose. In the second experiment the analysis showed a significant effect relative to the time delay since the accuracy of the correct responses 8 2~93009 decreased with time (F=104.02, df-3.33, p~0.001) and a significant effect in the dosage (F-3.96, df-3.33, p<0.001). A
post hoc analysis according to Newman Xeul showed that the rats provided significantly more frequent correct responses, if they were pretreated with 3 mg/kg of ipsapirone. In the third experiment the statistical analysis also showed a significant effect relative to the time delay, since the frequency of the correct responses decreased with time (F-55.647, df=3.33, p<0.001), a significant effect in the dosage (F=4.91, df=4.44, p<0.005) and a significant dosage: time interaction (F=2.19, df-12.132, p=0.01). A post hoc analysis showed that scopolamine has a significant adverse effect on the accuracy of responses in comparison with the control level. If the scopolamine administration was followed by an administration of ipsapirone (3 mg/kg) the test results relative to the accuracy of the responses were not significantly different from the control tests, i.e., the effect of scopolamine was completely canceled out.
These results show that ipsapirone improves the short-term memory and further can counteract the cognition-disturbing effects of scopalamine (a common, pharmacological model of the cognitive losses in the SDAT).
Based on the test results the above-described compounds bring about an improvement of cognitive functions both preventively and therapeutically analogously to hydergine and piracetam.
The invention also comprises pharmaceutical agents that contain the above-mentioned compounds in an effectit~e amount, their production and use for the treatment and prevention of the above-mentioned diseases. The pharmaceutical agents are produced according to processes known in the art, ~y the active ingredient being brought into the form of a pharmaceuttcal preparatlon, with suitable vehicle, auxiliary and/or addition substances, that is suitable for enteral or parenteral administration. The administration can take place orally or sublingually, as a solid in the form of capsules or tablets or as liquid in the form of solutions, suspensions, elixirs or emulsions or rectally in the form of suppositories or the form of injection solutions optionally also usable subcutaneously. As auxiliary agents for the desired pharmaceutical agent formulation the inert organic and inorganic vehicles known to one skilled in the art are suitable such as, for example, water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, etc. Optionally, moreover, they can contain preservatives, stabilizers, wetting agents, emulsifiers or salts to change the osmotic pressure or buffers.
The pharmaceutical preparations can be available in solid form, for example, as tablets, coated tablets, suppositories, capsules, or in liquid form, for example, as solutions, suspensions or emulsions or can be formulated as depot preparations.
As vehicle system interface-near auxiliary agents such as salts of bile acids or animal or vegetable phospholides, but also mixtures of them as well as liposomes or their components, can be used.
For oral use, tablets, coated tablets or capsules with talc and/or hydrocarbon vehicles or binders, such as, for example, lactose, corn or potato starch, are especially suitable. The use can also take place in liquid form, such as, for example, as juice, to which a sweetener is optionally added.
The dosage of the active ingredients can vary according to method of administration, age and weight of the patient, type and severity of the disease to be treated and similiar factors. The daily dose is 0.2-200 mg, and the dose can be given as a single dose administered all at once or subdivided into 2 or more daily doses. Generally the active ingredient is administered one to four times a day, optionally also together with other therapeutic active ingredients. The pharmaceutical agents according to the invention generally contain 0.01 to 20~ by weight of active ingredient relative to the preparation.
Claims (9)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. Use of antagonists or partial agonists on the 5-HT1a receptor or their physiologically compatible salts for the production of a pharmaceutical agent for the prevention and treatment of cognitive disorders.
2. Use according to claim 1 for the treatment and prevention of cognitive disorders in advanced age.
3. Use according to claim 1 for the prevention and treatment of AIDS-dependent dementia.
4. Use according to claim 1 for the treatment and prevention of Parkinson's-dependent dementia.
5. Use according to claim 1 for the prevention and treatment of Alzheimer's disease.
6. Use according to claims 1-5, characterized in that piperazine derivatives are used as active ingredients.
7. Use according to claims 1-6, wherein ipsapirone is used as active ingredient.
8. Use according to claims 1-6, wherein NAN 190 is used as active ingredient.
9. Pharmaceutical agent containing an effective amount of an antagonist or partial agonist on the 5-HT1a receptor or their physiologically compatible salts for the use according to claims 1-5.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4135551A DE4135551A1 (en) | 1991-08-31 | 1991-08-31 | USE OF ANTAGONISTS OR PARTIAL AGONISTS ON THE 5-HT1A RECEPTOR TO TREAT AND PREVENT COGNITIVE DISORDERS |
| DEP4135551.2 | 1991-08-31 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2093009A1 true CA2093009A1 (en) | 1993-03-01 |
Family
ID=6443608
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002093009A Abandoned CA2093009A1 (en) | 1991-08-31 | 1992-08-28 | Use of antagonists or partial agonists on the 5-ht 1a receptor for the treatment and prevention of cognitive disorders |
Country Status (10)
| Country | Link |
|---|---|
| EP (1) | EP0555446B1 (en) |
| JP (1) | JPH06501713A (en) |
| AT (1) | ATE182467T1 (en) |
| CA (1) | CA2093009A1 (en) |
| DE (2) | DE4135551A1 (en) |
| DK (1) | DK0555446T3 (en) |
| ES (1) | ES2135412T3 (en) |
| GR (1) | GR3031514T3 (en) |
| HU (1) | HUT63331A (en) |
| WO (1) | WO1993004681A1 (en) |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9223153D0 (en) * | 1992-11-05 | 1992-12-16 | Wyeth John & Brother Ltd | Piperazine derivatives |
| US5484788A (en) * | 1993-03-26 | 1996-01-16 | Beth Israel Hospital Association | Buspirone as a systemic immunosuppressant |
| EP0710481A1 (en) * | 1994-11-02 | 1996-05-08 | Duphar International Research B.V | Use of flesinoxan for cognition enhancement |
| US5637314A (en) * | 1995-06-07 | 1997-06-10 | Beth Israel Deaconess Medical Center, Inc. | Topical and systemic application of buspirone or derivatives thereof for treating atopic dermatitis |
| AU3883099A (en) | 1998-05-06 | 1999-11-23 | Duke University | Method of treating bladder and lower urinary tract syndromes |
| US7053092B2 (en) | 2001-01-29 | 2006-05-30 | Otsuka Pharmaceutical Co., Ltd. | 5-HT1a receptor subtype agonist |
| AR033485A1 (en) | 2001-09-25 | 2003-12-26 | Otsuka Pharma Co Ltd | MEDICINAL SUBSTANCE OF ARIPIPRAZOL OF LOW HYGROSCOPICITY AND PROCESS FOR THE PREPARATION OF THE SAME |
| US8703772B2 (en) | 2001-09-25 | 2014-04-22 | Otsuka Pharmaceutical Co., Ltd. | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
| PE20070523A1 (en) | 2005-09-12 | 2007-06-28 | Wyeth Corp | SUSTAINED RELEASE FORMULATION OF (8- {4- [3- (5-FLUORO-1H-INDOL-3-IL) -PROPYL] -PIPERAZIN-1-IL} -2-METHYL-4H-BENZO [1, 4] OXAZIN-3-ONA |
| GT200600416A (en) | 2005-09-12 | 2007-09-20 | SALTS SALCILATO AND GENTISATO OF A COMPOSITE OF PIPERAZINA | |
| GT200600414A (en) | 2005-09-12 | 2007-09-20 | PIPERAZINE COMPOSITE GLUCURANATE SALT | |
| US20130064770A1 (en) | 2010-05-28 | 2013-03-14 | Ge Healthcare Limited | Radiolabeled compounds and methods thereof |
| GB201112987D0 (en) | 2011-07-28 | 2011-09-14 | Ge Healthcare Ltd | Novel compound |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2355502A1 (en) * | 1976-06-23 | 1978-01-20 | Roussel Uclaf | APPLICATION AS A MEDICINAL PRODUCT OF A DERIVATIVE OF PIPERAZINE AND ITS SALTS |
| US4423049A (en) * | 1981-12-28 | 1983-12-27 | Mead Johnson & Company | 2-[4-[(4,4-Dialkyl-2,6-piperidinedion-1-yl)butyl]-1-piperazinyl]pyrimidines |
| US4897399A (en) * | 1988-04-20 | 1990-01-30 | Ciba-Geigy Corp. | Heterotertracyclic lactam derivatives, pharmaceutical compositions, and method of treating impaired memory and learning |
| GB2222768B (en) * | 1988-06-17 | 1992-01-22 | Nat Res Dev | Analgesic compounds and compositions |
| US4902687A (en) * | 1989-03-27 | 1990-02-20 | Eli Lilly And Company | Excitatory amino acid receptor antagonists |
| DE4039631A1 (en) * | 1990-12-12 | 1992-06-17 | Troponwerke Gmbh & Co Kg | Neuro-protective combination for treating cerebral ischaemia - contains a 5-HT1A receptor agonist and 5-HT2 receptor antagonist |
-
1991
- 1991-08-31 DE DE4135551A patent/DE4135551A1/en not_active Withdrawn
-
1992
- 1992-08-28 ES ES92918251T patent/ES2135412T3/en not_active Expired - Lifetime
- 1992-08-28 HU HU9301250A patent/HUT63331A/en unknown
- 1992-08-28 CA CA002093009A patent/CA2093009A1/en not_active Abandoned
- 1992-08-28 JP JP5504830A patent/JPH06501713A/en active Pending
- 1992-08-28 DE DE59209728T patent/DE59209728D1/en not_active Revoked
- 1992-08-28 DK DK92918251T patent/DK0555446T3/en active
- 1992-08-28 AT AT92918251T patent/ATE182467T1/en not_active IP Right Cessation
- 1992-08-28 WO PCT/DE1992/000720 patent/WO1993004681A1/en not_active Application Discontinuation
- 1992-08-28 EP EP92918251A patent/EP0555446B1/en not_active Revoked
-
1999
- 1999-10-13 GR GR990402609T patent/GR3031514T3/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| ES2135412T3 (en) | 1999-11-01 |
| DK0555446T3 (en) | 2000-01-31 |
| WO1993004681A1 (en) | 1993-03-18 |
| DE59209728D1 (en) | 1999-09-02 |
| DE4135551A1 (en) | 1993-03-04 |
| HU9301250D0 (en) | 1993-07-28 |
| ATE182467T1 (en) | 1999-08-15 |
| GR3031514T3 (en) | 2000-01-31 |
| JPH06501713A (en) | 1994-02-24 |
| EP0555446B1 (en) | 1999-07-28 |
| HUT63331A (en) | 1993-08-30 |
| EP0555446A1 (en) | 1993-08-18 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Discontinued |