WO1998018458A1 - Opthalmological compositions containing serotonin 5-ht1a receptor agonist and their use in the treatment of glaucoma - Google Patents
Opthalmological compositions containing serotonin 5-ht1a receptor agonist and their use in the treatment of glaucoma Download PDFInfo
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- WO1998018458A1 WO1998018458A1 PCT/US1997/015542 US9715542W WO9818458A1 WO 1998018458 A1 WO1998018458 A1 WO 1998018458A1 US 9715542 W US9715542 W US 9715542W WO 9818458 A1 WO9818458 A1 WO 9818458A1
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- serotonin
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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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
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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
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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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
Definitions
- the present invention relates to the use of compounds that activate the 5-HT 1A subtype of serotonin receptor and inhibit adenylyl cyclase activity in the eye to lower 0 intraocular pressure and treat glaucoma and ocular hypertension.
- Serotonin (5-hydroxytryptamine or 5-HT) is a natural neurotransmitter that acts on a family of serotonin receptors located in various tissues throughout the body, including the eye (Hoyer, D., Clarke, D.E., Fozard, J.R., Hartig, P.R., Martin, G.R., Mylecharane, E.J., Saxena, P R., Humphrey, P. A., "VII. International Union of Pharmacology Classification of Receptors for 5-Hydroxytryptamine (Serotonin),” Pharmacological Reviews , 46(2): 157- o 203 (1994)).
- Serotonin receptors include a family of receptor subtypes linked through their amino acid sequence homology and coupled to characteristic cellular responses through second messengers, cyclic adenosine monophosphate (cAMP), and inositol triphosphate (IP3) (Zifa, E., Fillion, G.; “5-Hydroxytryptamine Receptors", Pharmacological Reviews, 44(3):401-440 (1992)).
- cAMP cyclic adenosine monophosphate
- IP3 inositol triphosphate
- the 5-HT 1A receptor subtype can be 5 negatively coupled to adenylyl cyclase, the enzyme that synthesizes cAMP, so that its activation by a 5-HTtA agonist results in the inhibition of cAMP synthesis (Hoyer, D., Clarke, D.E., Fozard, J.R, Hartig, P.R., Martin, G.R., Mylecharane, E.J., Saxena, P.R., Humphrey, P. A., "VII. International Union of Pharmacology Classification of Receptors for 5-Hydroxytryptamine (Serotonin),” Pharmacological Reviews , 46(2): 157-203 (1994) o and Zifa, E. , Fillion, G. ; "5-Hydroxytryptamine Receptors", Pharmacological Reviews, 44(3):401-440 (1992)).
- SUBSTITUTE SHEET (RULE 23) Serotonin binding sites have been found in membrane preparations obtained from rabbit ciliary processes, the ocular tissue involved in aqueous humor secretion (Mallorga, P., Sugrue, M.F., "Characterization of serotonin receptors in the iris + ciliary body of the albino rabbit," Current Eye Research, 6(3):527-532 (1987) and Chidlow, G, DeSantis, L.M., Sharif, N.A., Osborne, N.N., “Characteristics of [ 3 H]5-Hydroxytryptamine Binding to Iris-Ciliary Body Tissue of the Rabbit" Investigative Ophthalmology & Visual Science, 36(11):2238-2245 (1995)).
- a population of 5-HT 1A receptors is present in rabbit ciliary processes and are negatively coupled to adenylyl cyclase (Barnett, N.L., Osborne, N.N., "The Presence of Serotonin (5-HT ⁇ ) Receptors Negatively Coupled to Adenylate Cyclase in Rabbit and Human Iris-Ciliary Processes", Exp. Eye Res., 57:209-216 (1993) and Tobi , A.B., Osborne, N.N., "Evidence for the Presence of Serotonin Receptors Negatively Coupled to Adenylate Cyclase in the Rabbit Iris-Ciliary Body," Journal of
- 5-HT 2 receptors exist in the rabbit iris-ciliary body (which includes the ciliary processes) (Chidlow, G, DeSantis, L.M., Sharif, N.A., Osborne, N.N., "Characteristics of [ H]5-Hy&oxytryptamine Binding to Iris-Ciliary Body Tissue of the Rabbit" Investigative Ophthalmology & Visual Science, 36(11):2238-2245 (1995)).
- ketanserin An antagonist of these receptors, ketanserin, has been shown to produce lowering of IOP; however, ketanserin also has affinity for alpha adrenergic receptors which could also be responsible for the IOP lowering effect (Chang, F.W., Burke, J.A., Potter, D.E., "Mechanism of the Ocular Hypotensive Action of Ketanserin," Journal of Ocular Pharmacology, 1(2): 137-147 (1985) and Costagliola, C, Scibelli, G, Fasano, M.L., Ferrara, L. A. , Mastiopasqua, L. ; "Effect of Oral Ketanserin Administration on Intraocular
- rabbit ciliary processes contain the message for the 5-HT 7 subtype serotonin receptor (Chidlow, G,
- this receptor In brain tissue, this receptor is positively coupled to adenylyl cyclase so its function in the ciliary process would appear to be diametrically opposed to that of the 5-HT 1A receptor (Hoyer, D., Clarke, D.E., Fozard, J.R., Hartig, P.R., Martin, G.R., Mylecharane, E.J., Saxena, P.R., Humphrey, P. A., "VII. International Union of Pharmacology Classification of Receptors for 5-Hydroxytryptamine (Serotonin)," Pharmacological Reviews, 46(2): 157- 203 (1994)).
- 5-HT 1A -like receptors that are positively coupled to adenylyl cyclase have also been reported (Zifa, E., Fillion, G; “5-Hydroxytryptamine Receptors", Pharmacological Reviews, 44(3):401-440 (1992)).
- 5-HT 1A receptor plays the dominant role for deterrrji ⁇ ing the direction of this effect and whether aqueous humor secretion is increased or decreased.
- the pharmacological activation of the serotonin receptor subtype, 5-HT 1A that is negatively coupled to adenylyl cyclase tissue, results in a lowering of IOP and thus are useful to treat glaucoma and ocular hypertension.
- DPAT 8-hydroxy dipropylamino tetraline
- 5-methoxy-N,N- dimethyltryptamine that have a relatively high affinity for serotonin binding sites of rabbit ciliary processes, were studied for their effect on IOP.
- Full agonists can be selected from, but not limited to, the following compounds: R(+) 8-hydroxy (DPAT); buspirone; N,N-dipropyl-5- carboxarrtidotryptamine; and 5-methoxy-N,N-dimethyltryptamine.
- Partial agonists at 5- HT 1A receptors include, but are not limited to, S(-)-8-hydroxy DPAT and spiroxatrine.
- the preferred route of a ⁇ ministration is topically to the affected eye.
- the dosage range for topical administration is generally between about 0.3 and about 3000 micrograms per eye ( ⁇ g/eye) and is preferably between about 1 and about 1000 ⁇ g/eye and most preferably between 30 and 300 ⁇ g/eye.
- the compounds of the present invention can be administered as solutions, suspensions, gels, solid inserts, or emulsions (dispersions) in a suitable vehicle.
- the compounds can be incorporated into various types of ophthalmic formulations for delivery to the eye. These compounds may be combined with ophthalmologically acceptable preservatives, surfactants, viscosity enhancers, penetration enhancers, buffers, sodium chloride, and water to form an aqueous, sterile ophthalmic suspension or solution.
- Ophthalmic solution formulations may be prepared by dissolving the compound in a physiologically acceptable isotonic aqueous buffer. Further, the ophthalmic solution may include an ophthalmologicalfy acceptable surfactant to assist in dissolving the compound.
- the ophthalmic solution may contain a thickener such as hydroxymethyl- cellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinylpyrrolidone, or the like, to improve the retention of the formulation in the conjunctival sac.
- a thickener such as hydroxymethyl- cellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinylpyrrolidone, or the like.
- the active ingredient is combined with a preservative in an appropriate vehicle, such as, mineral oil, liquid lanolin, or white petrolatum.
- Sterile ophthalmic gel formulations may be prepared by suspending the active ingredient in a hydrophilic base prepared from the combination of, for example, carbopol-940, or the like, according to the published formulations for analogous ophthalmic preparations; preservatives and tonicity agents can be incorporated.
- the compounds of the present invention are generally formulated at a concentration of about 0.001 to about 10 weight/volume % in an aqueous solution at a pH between about 4.5 and about 8.0.
- the compounds are preferably formulated at concentrations of about 0.0033 to 3.33% and, most preferably, at concentrations of about 0.1 to 1%. While the precise regimen is left to the discretion of the clinician, it is recommended that the compositions be topically applied by placing one or more drops in each eye one or more times per day.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
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Abstract
Methods and compositions for controlling intraocular pressure with 5-HT1A receptor agonists that inhibit adenylyl cyclase are disclosed.
Description
OPTHALMOLOGICAL COMPOSIΗONS CONTAINING SEROTONIN 5-HT1 A RECEPTOR AGONIST AND THEIR USE IN THE TREATMENT OF GLAUCOMA
The present invention relates to the use of compounds that activate the 5-HT1A subtype of serotonin receptor and inhibit adenylyl cyclase activity in the eye to lower 0 intraocular pressure and treat glaucoma and ocular hypertension.
Background of the Invention
s Serotonin (5-hydroxytryptamine or 5-HT) is a natural neurotransmitter that acts on a family of serotonin receptors located in various tissues throughout the body, including the eye (Hoyer, D., Clarke, D.E., Fozard, J.R., Hartig, P.R., Martin, G.R., Mylecharane, E.J., Saxena, P R., Humphrey, P. A., "VII. International Union of Pharmacology Classification of Receptors for 5-Hydroxytryptamine (Serotonin)," Pharmacological Reviews , 46(2): 157- o 203 (1994)). Serotonin receptors include a family of receptor subtypes linked through their amino acid sequence homology and coupled to characteristic cellular responses through second messengers, cyclic adenosine monophosphate (cAMP), and inositol triphosphate (IP3) (Zifa, E., Fillion, G.; "5-Hydroxytryptamine Receptors", Pharmacological Reviews, 44(3):401-440 (1992)). The 5-HT1A receptor subtype can be 5 negatively coupled to adenylyl cyclase, the enzyme that synthesizes cAMP, so that its activation by a 5-HTtA agonist results in the inhibition of cAMP synthesis (Hoyer, D., Clarke, D.E., Fozard, J.R, Hartig, P.R., Martin, G.R., Mylecharane, E.J., Saxena, P.R., Humphrey, P. A., "VII. International Union of Pharmacology Classification of Receptors for 5-Hydroxytryptamine (Serotonin)," Pharmacological Reviews , 46(2): 157-203 (1994) o and Zifa, E. , Fillion, G. ; "5-Hydroxytryptamine Receptors", Pharmacological Reviews, 44(3):401-440 (1992)).
SUBSTITUTE SHEET (RULE 23)
Serotonin binding sites have been found in membrane preparations obtained from rabbit ciliary processes, the ocular tissue involved in aqueous humor secretion (Mallorga, P., Sugrue, M.F., "Characterization of serotonin receptors in the iris + ciliary body of the albino rabbit," Current Eye Research, 6(3):527-532 (1987) and Chidlow, G, DeSantis, L.M., Sharif, N.A., Osborne, N.N., "Characteristics of [3H]5-Hydroxytryptamine Binding to Iris-Ciliary Body Tissue of the Rabbit" Investigative Ophthalmology & Visual Science, 36(11):2238-2245 (1995)). Competitive binding inhibition experiments using various ligands, with known or putative serotonin receptor subtype selectivity, were performed and the results indicated that the nature of one of the serotonin binding sites, i.e., receptors, located in rabbit ciliary processes is that of the 5-HT1A subtype (Mallorga, P., Sugrue,
M.F., "Characterization of serotonin receptors in the iris + ciliary body of the albino rabbit," Current Eye Research, 6(3):527-532 (1987) and Chidlow, G, DeSantis, L.M., Sharif, N.A., Osborne, N.N., "Characteristics of [3H]5-Hydroxytrypta ine Binding to Iris- Ciliary Body Tissue of the Rabbit" Investigative Ophthalmology & Visual Science, 36(11):2238-2245 (1995)). Thus, a population of 5-HT1A receptors is present in rabbit ciliary processes and are negatively coupled to adenylyl cyclase (Barnett, N.L., Osborne, N.N., "The Presence of Serotonin (5-HTι) Receptors Negatively Coupled to Adenylate Cyclase in Rabbit and Human Iris-Ciliary Processes", Exp. Eye Res., 57:209-216 (1993) and Tobi , A.B., Osborne, N.N., "Evidence for the Presence of Serotonin Receptors Negatively Coupled to Adenylate Cyclase in the Rabbit Iris-Ciliary Body," Journal of
Neurochemistry, 686-690 (1989)).
The question of the physiological relevance of these receptors can be raised. To this end, experiments have been performed to investigate the effect of ocularly applied serotonin on the intraocular pressure(IOP) of the rabbit eye (Meyer-Bothling, U., Bron,
A.J., Osborne, N.N.; "Topical Application of Serotonin or the
Intraocular Pressure in Rabbits," Investigative Ophthalmology & Visual Science, 34(10):3035-3042 (1993) and Krootila, K., Palkama, A, Uusitalo, H; "Effect of Serotonin and Its Antagonist (Ketanserin) on Intraocular Pressure in the Rabbit," Journal of Ocular Pharmacology, 3(4):279-290 (1987)). It has been reported that serotonin raised the IOP of
the rabbit, leading one to believe that the activation of 5-HT1A receptors in rabbit ciliary processes stimulates the secretion of aqueous humor and increases the IOP (Meyer- Bothling, U., Bron, A.J., Osborne, N.N.; "Topical Application of Serotonin or the 5-HTι- Agonist 5-CT Intraocular Pressure in Rabbits," Investigative Ophthalmology & Visual Science, 34(10):3035-3042 (1993)). However, the fact that serotonin acts on all subtypes of serotonin receptors makes the interpretation more difficult as it also lowered IOP in the rabbit according to another report (Krootila, K., Palkama, A., Uusitalo, H.; "Effect of Serotonin and Its Antagomst (Ketanserin) on Intraocular Pressure in the Rabbit," Journal of Ocular Pharmacology, 3(4):279-290 (1987)).
Additionally, it has been reported that 5-HT2 receptors exist in the rabbit iris-ciliary body (which includes the ciliary processes) (Chidlow, G, DeSantis, L.M., Sharif, N.A., Osborne, N.N., "Characteristics of [ H]5-Hy&oxytryptamine Binding to Iris-Ciliary Body Tissue of the Rabbit" Investigative Ophthalmology & Visual Science, 36(11):2238-2245 (1995)). An antagonist of these receptors, ketanserin, has been shown to produce lowering of IOP; however, ketanserin also has affinity for alpha adrenergic receptors which could also be responsible for the IOP lowering effect (Chang, F.W., Burke, J.A., Potter, D.E., "Mechanism of the Ocular Hypotensive Action of Ketanserin," Journal of Ocular Pharmacology, 1(2): 137-147 (1985) and Costagliola, C, Scibelli, G, Fasano, M.L., Ferrara, L. A. , Mastiopasqua, L. ; "Effect of Oral Ketanserin Administration on Intraocular
Pressure in Glaucomatous Patients," Exp. Eye Res., 52:507-510 (1991)). Thus, it is not clear whether 5-HT2 serotonin receptors play a major role in mediating the effect of ketanserin on IOP.
Using the techniques of molecular biology, it has been shown that rabbit ciliary processes contain the message for the 5-HT7 subtype serotonin receptor (Chidlow, G,
DeSantis, L.M., Sharif, N.A, Osborne, N.N., "Characteristics of [3H]5- Hydroxytryptamine Binding to Iris-Ciliary Body Tissue of the Rabbit" Investigative Ophthalmology & Visual Science, 36(11):2238-2245 (1995) and Osborne, N.N., Chidlow, G, "Do Beta-Adrenoceptors and Serotonin 5-HT1A Receptors Have Similar Functions in the Control of Intraocular Pressure in the Rabbit?" Ophthalmologica, 210:308-314
(1996)). However, no function in this tissue has yet been ascribed to this receptor. In brain tissue, this receptor is positively coupled to adenylyl cyclase so its function in the ciliary process would appear to be diametrically opposed to that of the 5-HT1A receptor (Hoyer, D., Clarke, D.E., Fozard, J.R., Hartig, P.R., Martin, G.R., Mylecharane, E.J., Saxena, P.R., Humphrey, P. A., "VII. International Union of Pharmacology Classification of Receptors for 5-Hydroxytryptamine (Serotonin)," Pharmacological Reviews, 46(2): 157- 203 (1994)). Moreover, 5-HT1A -like receptors that are positively coupled to adenylyl cyclase have also been reported (Zifa, E., Fillion, G; "5-Hydroxytryptamine Receptors", Pharmacological Reviews, 44(3):401-440 (1992)).
Summary of the Invention
It has now been unexpectedly discovered that compounds which act on the 5-HT1A subtype of serotonin receptors to inhibit adenylyl cyclase activity produce a lowering of intraocular pressure in mammalian species when applied topically to the eye. This pharmacological effect is useful to treat the conditions of glaucoma and ocular hypertension.
Description of Preferred Embodiments
It is believed that the net result from the stimulation of the multiple serotonin receptors in the ciliary processes of the eye depends on the relative importance of each receptor for regulating the physiological process of aqueous humor secretion and that the
5-HT1A receptor plays the dominant role for deterrrjiπing the direction of this effect and whether aqueous humor secretion is increased or decreased. Thus, the pharmacological activation of the serotonin receptor subtype, 5-HT1A, that is negatively coupled to adenylyl cyclase tissue, results in a lowering of IOP and thus are useful to treat glaucoma and ocular hypertension.
Two compounds, 8-hydroxy dipropylamino tetraline (DPAT) and 5-methoxy-N,N- dimethyltryptamine, that have a relatively high affinity for serotonin binding sites of rabbit ciliary processes, were studied for their effect on IOP. When applied to normotensive rabbit eyes, 8-hydroxy-DPAT was found to produce a decrease of IOP. Additionally, 5- methoxy-N,N-dimethyl tryptamine produced a decrease of IOP when applied topically to the (ocular) hypertensive monkey eye.
The compounds listed in Table 2 of Zifa, E., Fillion, G; "5-Hyα^oxytryptamine Receptors", Pharmacological Reviews , 44(3):401-440 (1992), which is incorporated herein by reference, can be used according to the present invention. Compounds which are full agonists (compounds which can completely activate the receptor to produce a maximal response) at 5-HT1A receptors are most preferred; partial agonists (compounds which produce a submaximal response when receptors are fully activated) being less preferred. Full agonists (to the extent known) can be selected from, but not limited to, the following compounds: R(+) 8-hydroxy (DPAT); buspirone; N,N-dipropyl-5- carboxarrtidotryptamine; and 5-methoxy-N,N-dimethyltryptamine. Partial agonists at 5- HT1A receptors include, but are not limited to, S(-)-8-hydroxy DPAT and spiroxatrine.
The preferred route of aα^ministration is topically to the affected eye. The dosage range for topical administration is generally between about 0.3 and about 3000 micrograms per eye (μg/eye) and is preferably between about 1 and about 1000 μg/eye and most preferably between 30 and 300 μg/eye. The compounds of the present invention can be administered as solutions, suspensions, gels, solid inserts, or emulsions (dispersions) in a suitable vehicle.
The compounds can be incorporated into various types of ophthalmic formulations for delivery to the eye. These compounds may be combined with ophthalmologically acceptable preservatives, surfactants, viscosity enhancers, penetration enhancers, buffers, sodium chloride, and water to form an aqueous, sterile ophthalmic suspension or solution. Ophthalmic solution formulations may be prepared by dissolving the compound in a
physiologically acceptable isotonic aqueous buffer. Further, the ophthalmic solution may include an ophthalmologicalfy acceptable surfactant to assist in dissolving the compound. Furthermore, the ophthalmic solution may contain a thickener such as hydroxymethyl- cellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinylpyrrolidone, or the like, to improve the retention of the formulation in the conjunctival sac. In order to prepare sterile ophthalmic ointment formulations, the active ingredient is combined with a preservative in an appropriate vehicle, such as, mineral oil, liquid lanolin, or white petrolatum. Sterile ophthalmic gel formulations may be prepared by suspending the active ingredient in a hydrophilic base prepared from the combination of, for example, carbopol-940, or the like, according to the published formulations for analogous ophthalmic preparations; preservatives and tonicity agents can be incorporated.
In forming compositions for topical administration, the compounds of the present invention are generally formulated at a concentration of about 0.001 to about 10 weight/volume % in an aqueous solution at a pH between about 4.5 and about 8.0. The compounds are preferably formulated at concentrations of about 0.0033 to 3.33% and, most preferably, at concentrations of about 0.1 to 1%. While the precise regimen is left to the discretion of the clinician, it is recommended that the compositions be topically applied by placing one or more drops in each eye one or more times per day.
Claims
1. A method for controlling intraocular pressure, which comprises, administering topically to the eye of a person suffering from glaucoma or ocular hypertension a composition comprising a therapeutically effective amount of a 5-HT1A receptor agonist that inhibits adenylyl cyclase.
2. The method of Claim 1 wherein the 5-HT1A receptor agonist is selected from the group consisting of R(+) 8-hydroxy dipropylamino tetraline and 5-methoxy-N,N- dimethyltryptamine.
3. The method of Claim 2 wherein the 5-HT1A receptor agonist is R(+) 8- hydroxy dipropylamino tetraline.
4. A topical, ophthalmic composition for controlling intraocular pressure, comprising a therapeutically effective amount of a 5-HT1A receptor agonist that inhibits adenylyl cyclase.
5. The composition of Claim 4 wherein the 5-HT1A receptor agonist is selected from the group consisting of R(+) 8-hydroxy dipropylamino tetraline and 5-methoxy-N,N- dimethyltryptamine.
6. The composition of Claim 5 wherein the 5-HT1A receptor agonist is R(+) 8- hydroxy dipropylamino tetraline.
Priority Applications (1)
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AU42492/97A AU4249297A (en) | 1996-10-31 | 1997-09-04 | Opthalmological compositions containing serotonin 5-ht1a receptor agonist and their use in the treatment of glaucoma |
Applications Claiming Priority (2)
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US2879096P | 1996-10-31 | 1996-10-31 | |
US60/028,790 | 1996-10-31 |
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Cited By (17)
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---|---|---|---|---|
WO2000016761A2 (en) * | 1998-09-18 | 2000-03-30 | Alcon Laboratories, Inc. | Serotonergic 5ht2 agonists for treating glaucoma |
WO2000074649A2 (en) * | 1999-06-03 | 2000-12-14 | Maxim Pharmaceuticals, Inc. | Ophthalmic histamine compositions and uses thereof |
WO2001070222A2 (en) * | 2000-03-17 | 2001-09-27 | Alcon Inc. | Compounds with 5-ht1a activity useful for treating disorders of the outer retina |
WO2004075895A1 (en) * | 2003-02-28 | 2004-09-10 | Sumitomo Pharmaceuticals Co., Ltd. | Ocular hypotensive agent |
US6881749B2 (en) | 2001-06-01 | 2005-04-19 | Alcon, Inc. | Pyranoindazoles and their use for the treatment of glaucoma |
US6884816B2 (en) * | 2001-08-31 | 2005-04-26 | Alcon, Inc. | Hydroxy substituted fused naphthyl-azoles and fused indeno-azoles and their use for the treatment of glaucoma |
US6960608B2 (en) | 2001-06-01 | 2005-11-01 | Alcon, Inc. | Fused indazoles and indoles and their use for the treatment of glaucoma |
US7060704B2 (en) | 1998-05-19 | 2006-06-13 | Alcon Manufacturing, Ltd. | Serotonergic 5HT7 receptor compounds for treating ocular and CNS disorders |
US7071225B2 (en) | 2001-06-01 | 2006-07-04 | Alcon, Inc. | Arylaminopropane analogues and their use for the treatment of glaucoma |
US7129257B1 (en) | 2003-12-15 | 2006-10-31 | Alcon, Inc. | Pyrazolo[3,4- e]benzoxazoles for the treatment of glaucoma |
US7208512B2 (en) | 2001-12-20 | 2007-04-24 | Alcon, Inc. | Benzodifuranimidazoline and benzofuranimidazoline derivatives and their use for the treatment of glaucoma |
US7268131B2 (en) | 2003-12-15 | 2007-09-11 | Alcon, Inc. | Substituted [1,4]oxazino[2,3-g]indazoles for the treatment of glaucoma |
US7338972B1 (en) | 2003-12-15 | 2008-03-04 | Alcon, Inc. | Substituted 1-alkylamino-1H-indazoles for the treatment of glaucoma |
US7396856B2 (en) | 2002-12-13 | 2008-07-08 | Alcon, Inc. | Benzopyran analogs and their use for the treatment of glaucoma |
US7425572B2 (en) | 2004-12-08 | 2008-09-16 | Alcon, Inc. | Use of dioxindoindazoles and dioxoloindazoles for treating glaucoma |
US7476687B2 (en) | 2003-11-26 | 2009-01-13 | Alcon, Inc. | Substituted furo[2,3-g]indazoles for the treatment of glaucoma |
US7763619B2 (en) | 2000-03-17 | 2010-07-27 | Alcon, Inc. | Compounds with 5-HT1A activity useful for treating disorders of the outer retina |
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1997
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- 1997-09-04 AU AU42492/97A patent/AU4249297A/en not_active Abandoned
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