Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 5 de 5
Filter
Add more filters










Database
Language
Publication year range
1.
Biol Pharm Bull ; 37(1): 130-6, 2014.
Article in English | MEDLINE | ID: mdl-24162843

ABSTRACT

KW-7158 is a novel therapeutic candidate for treating overactive bladder (OAB) with a unique mode of action: suppression of sensory afferent nerves. However, the molecular target of this compound remains unknown. We herein report the identification of the KW-7158 target to be equilibrative nucleoside transporter-1 (ENT1). A membrane protein expression library of ca. 7000 genes was expressed in a dorsal root ganglion cell line, which we had previously generated, and subjected to screening for binding with a fluorescent derivative that retains high binding activity to the target. The screening revealed that only cells transfected with an ENT1 expression vector exhibited significant binding. We next performed [(3)H]KW-7158 binding experiments and an adenosine influx assay and found that KW-7158 binds to and inhibits ENT1. To further demonstrate the pharmacological relevance, we evaluated other known ENT1 inhibitors (nitrobenzylthioinosine, dipyridamole, draflazine) in an in vitro bladder strip contraction assay and the rat spinal cord injury OAB model. We found that all of the inhibitors exhibited anti-OAB activities, of which the potencies were comparable to that of adenosine influx inhibition in vitro. These studies demonstrated that the pharmacological target of KW-7158 is ENT1, at least in the rat OAB model. Our results will aid understanding of the precise mechanism of action of this drug and may also shed new light on the use of the adenosine pathway for the treatment of OAB.


Subject(s)
Benzothiepins/pharmacology , Equilibrative Nucleoside Transporter 1/antagonists & inhibitors , Urinary Bladder, Overactive/metabolism , Afferent Pathways , Animals , Benzothiepins/therapeutic use , Cell Line , Female , Ganglia, Spinal/metabolism , Male , Rats , Rats, Inbred Strains , Urinary Bladder, Overactive/drug therapy
2.
Chem Pharm Bull (Tokyo) ; 57(3): 288-93, 2009 Mar.
Article in English | MEDLINE | ID: mdl-19252322

ABSTRACT

Novel conformationally restricted diamine derivatives containing imidazolidinylidene propanedinitrile were synthesized and evaluated for human and rat histamine H(3) receptor (H(3)R) binding affinities. Among them, compounds 2b, 2c, 2j, 2k and 2m were found to be potent ligands for both H(3)Rs with K(i) values in the sub-nanomolar range, and showed potent H(3) receptor antagonism.


Subject(s)
Diamines/chemical synthesis , Histamine H3 Antagonists/chemical synthesis , Imidazolidines/chemistry , Nitriles/chemistry , Receptors, Histamine H3/metabolism , Animals , Diamines/chemistry , Diamines/pharmacology , Histamine H3 Antagonists/chemistry , Histamine H3 Antagonists/pharmacology , Humans , Imidazolidines/chemical synthesis , Inhibitory Concentration 50 , Molecular Conformation , Nitriles/chemical synthesis , Rats
4.
J Med Chem ; 46(23): 4910-25, 2003 Nov 06.
Article in English | MEDLINE | ID: mdl-14584942

ABSTRACT

We have previously reported that a series of 4-[4-(N-substituted (thio)carbamoyl)-1-piperazinyl]-6,7-dimethoxyquinazoline derivatives were potent and selective inhibitors of platelet-derived growth factor receptor (PDGFR) phosphorylation and demonstrated several biological effects such as suppression of neointima formation following balloon injury in rat carotid artery by oral administration. Here, we investigated structure-activity relationships of the 6,7-dimethoxyquinazolinyl moiety. In regard to 6,7-dimethoxy groups, ethoxy analogues showed potent activity (IC(50) of 16b is 0.04 microM; IC(50) of 17a is 0.01 microM) and further extension of the alkyl group reduced activity. Interestingly, methoxyethoxy (IC(50) of 16j is 0.02 microM; IC(50) of 17h is 0.01 microM) and ethoxyethoxy (IC(50) of 17j is 0.02 micro M) analogues showed the most potent activity, suggesting that the inserted oxygen atom significantly interacts with beta-PDGFR. Among tricyclic quinazoline derivatives, the 2-oxoimidazo[4,5-e]quinazoline derivative 21a showed potent activity (IC(50) = 0.10 microM). Regarding replacements of quinazoline by other heterocyclic rings, pyrazolo[3,4-d]pyrimidine (39a, IC(50) = 0.17 microM) and quinoline (IC(50) of 40a is 0.18 microM; IC(50) of 40b is 0.09 microM) derivatives showed potent activity. Isoquinoline and some pyridopyrimidine derivatives were completely inactive; therefore, 1-aza has an important role. Also 7-aza and 8-aza substitution on the parent quinazoline ring has a detrimental effect on the interaction with beta-PDGFR. We also demonstrated that the substituents on the quinazoline ring possess major consequences for metabolic polymorphism. Although there existed extensive metabolizers and poor metabolizers in Sprague-Dawley rats administrated 6,7-dimethoxyquinazoline derivatives (1b and 1c), 6-(2-methoxy)ethoxy-7-methoxyquinazoline analogue 16k showed no metabolic polymorphism.


Subject(s)
Heterocyclic Compounds, 3-Ring/chemical synthesis , Piperazines/chemical synthesis , Quinazolines/chemical synthesis , Receptors, Platelet-Derived Growth Factor/metabolism , Administration, Oral , Animals , Depression, Chemical , Heterocyclic Compounds, 3-Ring/pharmacokinetics , Heterocyclic Compounds, 3-Ring/pharmacology , Injections, Intravenous , Male , Phosphorylation , Piperazines/pharmacokinetics , Piperazines/pharmacology , Polymorphism, Genetic , Quinazolines/pharmacokinetics , Quinazolines/pharmacology , Rats , Rats, Sprague-Dawley , Receptors, Platelet-Derived Growth Factor/genetics , Structure-Activity Relationship
SELECTION OF CITATIONS
SEARCH DETAIL
...