ABSTRACT
A series of 5-(piperidinylethyloxy)quinoline 5-HT(1) receptor ligands have been studied by elaboration of the series of dual 5-HT(1)-SSRIs reported previously. These new compounds display a different in vitro pharmacological profile with potent affinity across the 5-HT(1A), 5-HT(1B) and 5-HT(1D) receptors and selectivity against the serotonin transporter. Furthermore, they have improved pharmacokinetic profiles and CNS penetration.
Subject(s)
Quinolines/pharmacology , Receptors, Serotonin, 5-HT1/drug effects , Administration, Oral , Animals , Biological Availability , Ligands , Quinolines/administration & dosage , Quinolines/chemistry , Quinolines/pharmacokinetics , Rats , Structure-Activity RelationshipABSTRACT
Novel 2-methyl-5-quinolinyl-1-piperazinylalkyl-3,4-dihydro-2H-1,4-benzoxazin-3-ones showing high affinities for the 5-HT(1A/1B/1D) receptors coupled with potent 5-HT reuptake inhibitory activity have been discovered. This is the first report describing docking of the lead compound 6-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}-2H-1,4-benzoxazin-3(4H)-one 1, into a model of the 5-HT transporter and the 5-HT(1A) receptor model.
Subject(s)
Chemistry, Pharmaceutical/methods , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Serotonin 5-HT1 Receptor Antagonists , Administration, Oral , Animals , Chromatography/methods , Drug Design , Humans , Kinetics , Male , Models, Chemical , Molecular Conformation , Rats , Selective Serotonin Reuptake Inhibitors/pharmacologyABSTRACT
5-HT1 receptor antagonists have been discovered with good selectivity over the 5-HT transporter. This is the first report of highly potent, selective ligands for the 5-HT1A/B/D receptors with low intrinsic activity, which represent a useful set of molecules for further understanding the roles of the 5-HT1 receptor subtypes and providing new approaches for the treatment of depression.
Subject(s)
Piperazines/chemical synthesis , Quinolines/chemical synthesis , Serotonin 5-HT1 Receptor Antagonists , Animals , Blood-Brain Barrier/metabolism , Cerebral Cortex/metabolism , Humans , In Vitro Techniques , Piperazines/pharmacokinetics , Piperazines/pharmacology , Quinolines/pharmacokinetics , Quinolines/pharmacology , Radioligand Assay , Rats , Recombinant Proteins/pharmacology , Structure-Activity RelationshipABSTRACT
A series of 5-(piperidinylethyloxy)quinoline 5-HT(1) receptor ligands have been studied by elaboration of the series of dual 5-HT(1)-SSRIs reported previously. These new compounds display a different pharmacological profile with potent affinity across the 5-HT(1A), 5-HT(1B) and 5-HT(1D) receptors and selectivity against the serotonin transporter. Furthermore, they have improved pharmacokinetic profiles and CNS penetration.
Subject(s)
Receptors, Serotonin/metabolism , Serotonin Agents/metabolism , Administration, Oral , Biological Availability , Ligands , Serotonin Agents/pharmacokineticsABSTRACT
RATIONALE: The delay in onset and treatment resistance of subpopulations of depressed patients to conventional serotonin reuptake inhibitors has lead to new drug development strategies to produce agents with improved antidepressant efficacy. OBJECTIVES: We report the in vivo characterization of the novel 5-HT(1A/1B) autoreceptor antagonist/5-HT transporter inhibitor (6-[(1-{2-[(2-methyl-5-quinolinyl)oxy]ethyl}-4-piperidinyl)methyl]-2H-1,4-benzoxazin-3(4H)-one), SB-649915-B. MATERIALS AND METHODS: Ex vivo binding was used to ascertain 5-HT(1A) receptor and serotonin transporter occupancy. 8-OH-DPAT-induced hyperlocomotion and SKF-99101-induced elevation of seizure threshold were used as markers of central blockade of 5-HT(1A) and 5-HT(1B) receptors, respectively. In vivo electrophysiology in the rat dorsal raphe and microdialysis in freely moving guinea pigs and rats were used to evaluate the functional outcome of SB-649915-B. RESULTS: SB-649915-B (1-10 mg/kg p.o.) produced a dose-related inhibition of 5-HT(1A) receptor radioligand binding and inhibited ex vivo [(3)H]5-HT uptake in both guinea pig and rat cortex. SB-649915-B (0.1-10 mg/kg p.o.) reversed both 8-OH-DPAT-induced hyperlocomotor activity and SKF-99101-induced elevation of seizure threshold in the rat, demonstrating in vivo blockade of both 5-HT(1A) and 5-HT(1B) receptors, respectively. SB-649915-B (0.1-3 mg/kg i.v.) produced no change in raphe 5-HT neuronal cell firing per se but attenuated the inhibitory effect of 8-OH-DPAT. Acute administration of SB-649915-B resulted in increases (approximately two- to threefold) in extracellular 5-HT in the cortex of rats and the dentate gyrus and cortex of guinea pigs. CONCLUSIONS: Based on these data, one may speculate that the 5-HT autoreceptor antagonist/5-HT transport inhibitor SB-649915-B will have therapeutic efficacy in the treatment of affective disorders with the potential for a faster onset of action compared to current selective serotonin reuptake inhibitors.
Subject(s)
Benzoxazines/pharmacology , Piperidines/pharmacology , Quinolines/pharmacology , Selective Serotonin Reuptake Inhibitors/pharmacology , Serotonin 5-HT1 Receptor Antagonists , Serotonin Plasma Membrane Transport Proteins/drug effects , Animals , Dentate Gyrus/drug effects , Dentate Gyrus/metabolism , Dose-Response Relationship, Drug , Electrophysiology , Electroshock , Guinea Pigs , Locomotion/drug effects , Male , Microdialysis , Mood Disorders/drug therapy , Neurons/drug effects , Prefrontal Cortex/drug effects , Prefrontal Cortex/metabolism , Radioligand Assay , Raphe Nuclei , Rats , Rats, Sprague-Dawley , Seizures , Serotonin/metabolism , Serotonin Plasma Membrane Transport Proteins/metabolism , Species SpecificityABSTRACT
Investigation of halogen substitution in lead compound 1 has led to the identification of analogues which combine high affinity for 5-HT(1A) receptors and potent serotonin reuptake inhibitory activity. Several compounds show an improved selectivity over 5-HT(1B) and 5-HT(1D) receptors and a superior pharmacokinetic profile in the rat.
Subject(s)
Benzoxazines/chemical synthesis , Benzoxazines/pharmacology , Receptor, Serotonin, 5-HT1A/drug effects , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Selective Serotonin Reuptake Inhibitors/pharmacology , Serotonin Antagonists/chemical synthesis , Serotonin Antagonists/pharmacology , Animals , Binding, Competitive/drug effects , CHO Cells , Callithrix , Cell Line , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Cricetinae , Cricetulus , Guinea Pigs , Humans , Indicators and Reagents , Magnetic Resonance Spectroscopy , Mass Spectrometry , Models, Molecular , Piperazines/pharmacology , Pyridines/pharmacology , Radioligand Assay , Rats , Receptor, Serotonin, 5-HT1B/drug effects , Receptor, Serotonin, 5-HT1D/drug effects , Synaptosomes/drug effectsABSTRACT
An SAR study around the mixed 5-HT1ABD receptor antagonist SB-272183 found that introduction of cis-2,6-dimethyl substitution onto the piperazine ring was a key structural change, which imparted a combination of both excellent selectivity over the 5-HT1A and 5-HT1D receptors and low intrinsic activity. This led to the identification of the selective 5-HT1B receptor antagonist SB-616234.
Subject(s)
Serotonin 5-HT1 Receptor Antagonists , Serotonin Antagonists/chemical synthesis , Animals , Humans , Ligands , Microsomes, Liver , Rats , Serotonin Antagonists/pharmacology , Structure-Activity RelationshipABSTRACT
The novel 8-piperazinyl-2,3-dihydropyrroloisoquinoline template was synthesized in nine steps. The template was N-substituted to give a series of compounds showing binding to human cloned 5-HT1A, 5-HT1B and 5-HT1D receptors with pKi's greater than 9 and selectivities up to 1000-fold against other serotonin, dopamine and adrenergic receptors. Several compounds were shown to possess weak partial agonist activity in cloned receptors, which translated to antagonism in in vitro studies.
Subject(s)
Isoquinolines/chemical synthesis , Receptors, Serotonin/drug effects , Serotonin Antagonists/chemical synthesis , Serotonin Receptor Agonists/chemical synthesis , Administration, Oral , Animals , Biological Availability , Brain Chemistry , Isoquinolines/pharmacokinetics , Isoquinolines/pharmacology , Ligands , Rats , Receptor, Serotonin, 5-HT1A , Receptor, Serotonin, 5-HT1B , Receptor, Serotonin, 5-HT1D , Serotonin Antagonists/pharmacokinetics , Serotonin Antagonists/pharmacology , Serotonin Receptor Agonists/pharmacokinetics , Serotonin Receptor Agonists/pharmacology , Structure-Activity RelationshipABSTRACT
A series of 5-(piperidinylethyloxy)quinoline 5-hydroxytryptamine(1D) (5-HT(1D)) receptor antagonists have been discovered from elaboration of the series of dual 5-hydroxytryptamine(1)-selective serotonin reuptake inhibitors (5HT(1)-SSRIs) reported previously. This is the first report of highly potent, selective antagonists for the 5-HT(1D) receptor, which represents an extremely useful set of pharmacological tools for further understanding the roles of the 5-HT(1) receptor subtypes.
Subject(s)
Piperazines/chemical synthesis , Quinolines/chemical synthesis , Serotonin 5-HT1 Receptor Antagonists , Animals , Binding, Competitive , CHO Cells , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Cricetinae , Cricetulus , In Vitro Techniques , Piperazines/chemistry , Piperazines/pharmacology , Quinolines/chemistry , Quinolines/pharmacology , Radioligand Assay , Rats , Serotonin 5-HT1 Receptor Agonists , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Selective Serotonin Reuptake Inhibitors/chemistry , Selective Serotonin Reuptake Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
Starting from a high throughput screening hit, a series of 3,4-dihydro-2H-benzoxazinones has been identified with both high affinity for the 5-HT(1A) receptor and potent 5-HT reuptake inhibitory activity. The 5-(2-methyl)quinolinyloxy derivative combined high 5-HT(1A/1B/1D) receptor affinities with low intrinsic activity and potent inhibition of the 5-HT reuptake site (pK(i)8.2). This compound also had good oral bioavailability and brain penetration in the rat.
Subject(s)
Benzoxazines/chemical synthesis , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Serotonin 5-HT1 Receptor Antagonists , Animals , Benzoxazines/pharmacology , Biological Availability , Brain/metabolism , Cell Line , Drug Stability , Humans , Radioligand Assay , Rats , Selective Serotonin Reuptake Inhibitors/pharmacology , Structure-Activity Relationship , Synaptosomes/metabolismABSTRACT
1 (6-((R)-2-[2-[4-(4-Chloro-phenoxy)-piperidin-1-yl]-ethyl]-pyrrolidine-1-sulphonyl)-1H-indole hydrochloride) (SB-656104-A), a novel 5-hydroxytryptamine (5-HT(7)) receptor antagonist, potently inhibited [(3)H]-SB-269970 binding to the human cloned 5-HT(7(a)) (pK(i) 8.7+/-0.1) and 5-HT(7(b)) (pK(i) 8.5+/-0.2) receptor variants and the rat native receptor (pK(i) 8.8+/-0.2). The compound displayed at least 30-fold selectivity for the human 5-HT(7(a)) receptor versus other human cloned 5-HT receptors apart from the 5-HT(1D) receptor ( approximately 10-fold selective). 2 SB-656104-A antagonised competitively the 5-carboxamidotryptamine (5-CT)-induced accumulation of cyclic AMP in h5-HT(7(a))/HEK293 cells with a pA(2) of 8.5. 3 Following a constant rate iv infusion to steady state in rats, SB-656104 had a blood clearance (CL(b)) of 58+/-6 ml min(-1) kg(-1) and was CNS penetrant with a steady-state brain : blood ratio of 0.9 : 1. Following i.p. administration to rats (10 mg kg(-1)), the compound displayed a t(1/2) of 1.4 h with mean brain and blood concentrations (at 1 h after dosing) of 0.80 and 1.0 micro M, respectively. 4 SB-656104-A produced a significant reversal of the 5-CT-induced hypothermic effect in guinea pigs, a pharmacodynamic model of 5-HT(7) receptor interaction in vivo (ED(50) 2 mg kg(-1)). 5 SB-656104-A, administered to rats at the beginning of the sleep period (CT 0), significantly increased the latency to onset of rapid eye movement (REM) sleep at 30 mg kg(-1) i.p. (+93%) and reduced the total amount of REM sleep at 10 and 30 mg kg(-1) i.p. with no significant effect on the latency to, or amount of, non-REM sleep. SB-269970-A produced qualitatively similar effects in the same study. 6 In summary, SB-656104-A is a novel 5-HT(7) receptor antagonist which has been utilised in the present study to provide further evidence for a role for 5-HT(7) receptors in the modulation of REM sleep.
