RESUMO
BACKGROUND AND PURPOSE: M1 muscarinic ACh receptors (mAChRs) represent an attractive drug target for the treatment of cognitive deficits associated with diseases such as Alzheimer's disease and schizophrenia. However, the discovery of subtype-selective mAChR agonists has been hampered by the high degree of conservation of the orthosteric ACh-binding site among mAChR subtypes. The advent of functional screening assays has enabled the identification of agonists such as AC-42 (4-n-butyl-1-[4-(2-methylphenyl)-4-oxo-1-butyl]-piperidine), which bind to an allosteric site and selectively activate the M(1) mAChR subtype. However, studies with this compound have been limited to recombinantly expressed mAChRs. EXPERIMENTAL APPROACH: In this study, we have compared the pharmacological profile of AC-42 and a close structural analogue, 77-LH-28-1 (1-[3-(4-butyl-1-piperidinyl)propyl]-3,4-dihydro-2(1H)-quinolinone) at human recombinant, and rat native, mAChRs by calcium mobilization, inositol phosphate accumulation and both in vitro and in vivo electrophysiology. KEY RESULTS: Calcium mobilization and inositol phosphate accumulation assays revealed that both AC-42 and 77-LH-28-1 display high selectivity to activate the M1 mAChR over other mAChR subtypes. Furthermore, 77-LH-28-1, but not AC-42, acted as an agonist at rat hippocampal M1 receptors, as demonstrated by its ability to increase cell firing and initiate gamma frequency network oscillations. Finally, 77-LH-28-1 stimulated cell firing in the rat hippocampus in vivo following subcutaneous administration. CONCLUSIONS AND IMPLICATIONS: These data suggest that 77-LH-28-1 is a potent, selective, bioavailable and brain-penetrant agonist at the M1 mAChR and therefore that it represents a better tool than AC-42, with which to study the pharmacology of the M1 mAChR.
Assuntos
Hipocampo/efeitos dos fármacos , Agonistas Muscarínicos/farmacologia , Piperidinas/farmacologia , Quinolonas/farmacologia , Receptores Muscarínicos/efeitos dos fármacos , Potenciais de Ação , Animais , Células CHO , Sinalização do Cálcio/efeitos dos fármacos , Cricetinae , Cricetulus , Relação Dose-Resposta a Droga , Hipocampo/metabolismo , Humanos , Injeções Intraperitoneais , Injeções Subcutâneas , Fosfatos de Inositol/metabolismo , Agonistas Muscarínicos/administração & dosagem , Agonistas Muscarínicos/farmacocinética , Técnicas de Patch-Clamp , Permeabilidade , Piperidinas/administração & dosagem , Piperidinas/farmacocinética , Quinolonas/administração & dosagem , Quinolonas/farmacocinética , Ratos , Ratos Sprague-Dawley , Receptor Muscarínico M1 , Receptores Muscarínicos/genética , Receptores Muscarínicos/metabolismo , Proteínas Recombinantes/agonistas , Fatores de Tempo , TransfecçãoRESUMO
The preparation and biological evaluation of a series of indolopiperidine CCR2B receptor antagonists possessing a conformationally restricted C-5 linker chain in combination with a restricted piperidine ring are described. Compared to the parent compound 1, analogue 8 shows a dramatic improvement in selectivity against a range of 5-HT and dopaminergic receptors.
Assuntos
Indóis/farmacologia , Piperidinas/farmacologia , Receptores de Quimiocinas/antagonistas & inibidores , Antagonistas de Dopamina/síntese química , Antagonistas de Dopamina/química , Antagonistas de Dopamina/farmacologia , Indóis/síntese química , Indóis/química , Conformação Molecular , Piperidinas/síntese química , Piperidinas/química , Receptores CCR2 , Receptores de Quimiocinas/metabolismo , Antagonistas da Serotonina/síntese química , Antagonistas da Serotonina/química , Antagonistas da Serotonina/farmacologia , Relação Estrutura-AtividadeRESUMO
SB-243213 (5-methyl-1-[[-2-[(2-methyl-3-pyridyl)oxy]-5-pyridyl]carbamoyl]-6-trifluoromethylindoline hydrochloride) is a new, selective 5-hydroxytryptamine (5-HT)2C receptor inverse agonist. SB-243213 has high affinity for the human 5-HT2C receptor (pK(i) 9.37) and greater than a 100-fold selectivity over a wide range of neurotransmitter receptors, enzymes and ion channels. In in vitro functional studies, SB-243213 acted as an inverse agonist at the human 5-HT2C receptor with a pK(b) of 9.8. In in vivo studies, SB-243213 was a potent inhibitor of central 5-HT2C receptor-mediated function in rats, blocking meta-chlorophenylpiperazine-induced hypolocomotion with an ID50 of 1.1 mg/kg p.o. and a long duration of action (>8 h). In rats, SB-243213 exhibited anxiolytic-like activity in both the social interaction and Geller-Seifter conflict tests. Importantly, unlike diazepam, chronic administration of SB-243213 did not result in the development of either tolerance to the anxiolytic-like effects or withdrawal anxiogenesis. Furthermore, in rodents, SB-243213 did not affect seizure threshold, did not increase body weight or induce catalepsy, but attenuated the haloperidol-induced catalepsy. SB-243213 did not affect amphetamine-, MK-801- or phencyclidine-induced hyperactivity. In conclusion, SB-243213 may possess an improved anxiolytic profile compared to benzodiazepines. SB-243213 also modulates dopaminergic transmission, lacks pro-psychotic properties and may have utility in the treatment of schizophrenia and motor disorders.
Assuntos
Ansiolíticos/farmacologia , Indóis/farmacologia , Atividade Motora/efeitos dos fármacos , Piridinas/farmacologia , Receptores de Serotonina , Comportamento Social , Animais , Ansiolíticos/efeitos adversos , Ansiolíticos/uso terapêutico , Ansiedade/tratamento farmacológico , Ansiedade/psicologia , Catalepsia/induzido quimicamente , Catalepsia/tratamento farmacológico , Diazepam/efeitos adversos , Relação Dose-Resposta a Droga , Tolerância a Medicamentos/fisiologia , Humanos , Indóis/uso terapêutico , Fosfatos de Inositol/metabolismo , Masculino , Atividade Motora/fisiologia , Piridinas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Receptor 5-HT2C de Serotonina , Receptores de Serotonina/metabolismo , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Síndrome de Abstinência a Substâncias/psicologiaRESUMO
A weak HTS hit at the CCR2B receptor has been converted into a potent antagonist by array SAR studies. Selectivity over the closely related CCR5 receptor is also achieved.
Assuntos
Amidas/química , Amidas/farmacologia , Quimiocina CCL2/metabolismo , Indóis/farmacologia , Piperidinas/farmacologia , Receptores de Quimiocinas/antagonistas & inibidores , Amidas/síntese química , Amidas/metabolismo , Quimiocina CCL2/química , Quimiotaxia de Leucócito/efeitos dos fármacos , Humanos , Indóis/síntese química , Indóis/química , Indóis/metabolismo , Cinética , Ligantes , Estrutura Molecular , Monócitos/efeitos dos fármacos , Piperidinas/síntese química , Piperidinas/química , Piperidinas/metabolismo , Receptores CCR2 , Receptores CCR5/metabolismo , Receptores de Quimiocinas/química , Receptores de Quimiocinas/metabolismo , Relação Estrutura-AtividadeRESUMO
Bisaryl ethers have been identified with excellent 5-HT2C affinity and selectivity over both 5-HT2A and 5-HT2B receptors. Compounds such as 11, 27 and 38 have potent oral activity in a centrally mediated pharmacodynamic model of 5-HT2C function and their potential as novel non-sedating anxiolytic and antidepressants is under investigation.
Assuntos
Aminopiridinas/síntese química , Aminopiridinas/farmacologia , Indóis/síntese química , Indóis/farmacologia , Receptores de Serotonina/metabolismo , Antagonistas da Serotonina/síntese química , Administração Oral , Aminopiridinas/administração & dosagem , Aminopiridinas/química , Animais , Ansiolíticos/administração & dosagem , Ansiolíticos/síntese química , Ansiolíticos/química , Ansiolíticos/farmacologia , Antidepressivos/administração & dosagem , Antidepressivos/síntese química , Antidepressivos/química , Antidepressivos/farmacologia , Desenho de Fármacos , Humanos , Indóis/administração & dosagem , Indóis/química , Cinética , Estrutura Molecular , Atividade Motora/efeitos dos fármacos , Ratos , Receptor 5-HT2C de Serotonina , Receptores de Serotonina/química , Antagonistas da Serotonina/administração & dosagem , Antagonistas da Serotonina/química , Antagonistas da Serotonina/farmacologia , Relação Estrutura-AtividadeRESUMO
Bisarylmethoxyethers have been identified with nanomolar 5-HT2C affinity and selectivity over both 5-HT2A and 5-HT2B receptors. Compounds such as 1, 2, 8, 12, 14 and 18 have potent oral activity in a centrally mediated pharmacodynamic model of 5-HT2C function and their therapeutic potential is currently under further investigation.
Assuntos
Aminopiridinas/síntese química , Aminopiridinas/farmacologia , Indóis/síntese química , Indóis/farmacologia , Receptores de Serotonina/metabolismo , Antagonistas da Serotonina/síntese química , Antagonistas da Serotonina/farmacologia , Aminopiridinas/administração & dosagem , Aminopiridinas/química , Animais , Desenho de Fármacos , Indóis/administração & dosagem , Indóis/química , Cinética , Estrutura Molecular , Atividade Motora/efeitos dos fármacos , Ratos , Receptor 5-HT2C de Serotonina , Antagonistas da Serotonina/administração & dosagem , Antagonistas da Serotonina/química , Relação Estrutura-AtividadeRESUMO
The evolution, synthesis, and biological activity of a novel series of 5-HT(2C) receptor inverse agonists are reported. Biarylcarbamoylindolines have been identified with excellent 5-HT(2C) affinity and selectivity over 5-HT(2A) receptors. In addition, (pyridyloxypyridyl)carbamoylindolines have been discovered with additional selectivity over the closely related 5-HT(2B) receptor. Compounds from this series are inverse agonists at the human cloned 5-HT(2C) receptor, completely abolishing basal activity in a functional assay. The new series have reduced P450 inhibitory liability compared to a previously described series of 1-(3-pyridylcarbamoyl)indolines (Bromidge et al. J. Med. Chem. 1998, 41, 1598) from which they evolved. Compounds from this series showed excellent oral activity in a rat mCPP hypolocomotion model and in animal models of anxiety. On the basis of their favorable biological profile, 32 (SB-228357) and 40 (SB-243213) have been selected for further evaluation to determine their therapeutic potential for the treatment of CNS disorders such as depression and anxiety.
Assuntos
Ansiolíticos/síntese química , Antidepressivos/síntese química , Indóis/síntese química , Piridinas/síntese química , Receptores de Serotonina/metabolismo , Agonistas do Receptor de Serotonina/síntese química , Administração Oral , Animais , Ansiolíticos/química , Ansiolíticos/metabolismo , Ansiolíticos/farmacologia , Antidepressivos/química , Antidepressivos/metabolismo , Antidepressivos/farmacologia , Linhagem Celular , Humanos , Indóis/química , Indóis/metabolismo , Indóis/farmacologia , Modelos Moleculares , Atividade Motora/efeitos dos fármacos , Piridinas/química , Piridinas/metabolismo , Piridinas/farmacologia , Ensaio Radioligante , Ratos , Receptor 5-HT2A de Serotonina , Receptor 5-HT2B de Serotonina , Receptor 5-HT2C de Serotonina , Agonistas do Receptor de Serotonina/química , Agonistas do Receptor de Serotonina/metabolismo , Agonistas do Receptor de Serotonina/farmacologia , Relação Estrutura-AtividadeAssuntos
Fenóis/síntese química , Receptores de Serotonina/efeitos dos fármacos , Antagonistas da Serotonina/síntese química , Sulfonamidas/síntese química , Linhagem Celular , Humanos , Modelos Moleculares , Fenóis/química , Fenóis/metabolismo , Ensaio Radioligante , Receptores de Serotonina/metabolismo , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/metabolismo , Antagonistas da Serotonina/química , Antagonistas da Serotonina/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/metabolismoRESUMO
A model series of 5-HT2C antagonists have been prepared by rapid parallel synthesis. These N-substituted phenyl-N'-pyridin-3-yl ureas were found to have a range of 5-HT2C receptor affinities and selectivities over the closely related 5-HT2A receptor. Extrapolation of simple SAR, derived from this set of compounds, to the more active but synthetically more complex 1-(3-pyridylcarbamoyl)indoline series allowed us to target optimal substitution patterns and identify potent and selective 5-HT(2C/2B) antagonists.
Assuntos
Compostos de Fenilureia/química , Compostos de Fenilureia/farmacologia , Piridinas/química , Piridinas/farmacologia , Receptores de Serotonina/efeitos dos fármacos , Antagonistas da Serotonina/química , Antagonistas da Serotonina/farmacologia , Animais , Humanos , Técnicas In Vitro , Cinética , Espectroscopia de Ressonância Magnética , Modelos Químicos , Compostos de Fenilureia/síntese química , Piridinas/síntese química , Receptor 5-HT2B de Serotonina , Receptor 5-HT2C de Serotonina , Receptores de Serotonina/metabolismo , Antagonistas da Serotonina/síntese química , Relação Estrutura-AtividadeRESUMO
1. The functional profile of the long form of the human cloned 5-HT7 receptor (designated h5-HT7(a)) was investigated using a number of 5-HT receptor agonists and antagonists and compared with its binding profile. Receptor function was measured using adenylyl cyclase activity in washed membranes from HEK293 cells stably expressing the recombinant h5-HT7(a) receptor. 2. The receptor binding profile, determined by competition with [3H]-5-CT, was consistent with that previously reported for the h5-HT7(a) receptor. The selective 5-HT7 receptor antagonist SB-258719 ((R)-3,N-Dimethyl-N-[1-methyl-3-(4-methylpiperidin-1-yl)propyl]ben zene sulfonamide) displayed high affinity (pKi 7.5) for the receptor. 3. In the adenylyl cyclase functional assay, 5-CT and 8-OH-DPAT were both full agonists compared to 5-HT and the rank order of potency for agonists (5-CT > 5-HT > 8-OH-DPAT) was the same in functional and binding studies. 4. Risperidone, methiothepin, mesulergine, clozapine, olanzapine, ketanserin and SB-258719 antagonised surmountably 5-CT-stimulated adenylyl cyclase activity. Schild analysis of the antagonism by SB-258719 gave a pA2 of 7.2+/-0.2 and slope not significantly different from 1, consistent with competitive antagonism. 5. The same antagonists also inhibited basal adenylyl cyclase activity with a rank order of potency in agreement with those for antagonist potency and binding affinity. Both SB-258719 and mesulergine displayed apparent partial inverse agonist profiles compared to the other antagonists tested. These inhibitory effects of antagonists appear to be 5-HT7 receptor-mediated and to reflect inverse agonism. 6. It is concluded that in this expression system, the h5-HT7(a) receptor shows the expected binding and functional profile and displays constitutive activity, revealing inverse agonist activity for a range of antagonists.
Assuntos
Piperidinas/farmacologia , Receptores de Serotonina/metabolismo , Antagonistas da Serotonina/farmacologia , Sulfonamidas/farmacologia , Adenilil Ciclases/metabolismo , Linhagem Celular , Clonagem Molecular , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Humanos , Ligação Proteica , Receptores de Serotonina/genética , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismoRESUMO
The synthesis, biological activity, and molecular modeling of a novel series of substituted 1-(3-pyridylcarbamoyl)indolines are reported. These compounds are isosteres of the previously published indole urea 1 (SB-206553) and illustrate the use of aromatic disubstitution as a replacement for fused five-membered rings in the context of 5-HT2C/2B receptor antagonists. By targeting a region of space previously identified as sterically allowed at the 5-HT2C receptor but disallowed at the 5-HT2A receptor, we have identified a number of compounds which are the most potent and selective 5-HT2C/2B receptor antagonists yet reported. 46 (SB-221284) was selected on the basis of its overall biological profile for further evaluation as a novel, potential nonsedating anxiolytic agent. A CoMFA analysis of these compounds produced a model with good predictive value and in addition good qualitative agreement with both our 5-HT2C receptor model and our proposed binding mode for this class of ligands within that model.
Assuntos
Ansiolíticos , Indóis , Modelos Moleculares , Piridinas , Receptores de Serotonina/efeitos dos fármacos , Antagonistas da Serotonina , Animais , Ansiolíticos/síntese química , Ansiolíticos/química , Ansiolíticos/metabolismo , Ansiolíticos/farmacologia , Condicionamento Operante/efeitos dos fármacos , Conflito Psicológico , Indóis/síntese química , Indóis/química , Indóis/metabolismo , Indóis/farmacologia , Masculino , Atividade Motora/efeitos dos fármacos , Piridinas/síntese química , Piridinas/química , Piridinas/metabolismo , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor 5-HT2B de Serotonina , Receptor 5-HT2C de Serotonina , Receptores de Serotonina/metabolismo , Antagonistas da Serotonina/síntese química , Antagonistas da Serotonina/química , Antagonistas da Serotonina/metabolismo , Antagonistas da Serotonina/farmacologia , Comportamento Social , Relação Estrutura-AtividadeAssuntos
Piperidinas/síntese química , Receptores de Serotonina/efeitos dos fármacos , Antagonistas da Serotonina/síntese química , Sulfonamidas/síntese química , Adenilil Ciclases/metabolismo , Ligação Competitiva , Linhagem Celular , Expressão Gênica , Humanos , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Piperidinas/farmacologia , Receptores de Serotonina/genética , Receptores de Serotonina/fisiologia , Antagonistas da Serotonina/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonamidas/farmacologiaAssuntos
Aminopiridinas/farmacologia , Barreira Hematoencefálica , Indóis/farmacologia , Receptores de Serotonina/efeitos dos fármacos , Antagonistas da Serotonina/farmacologia , Aminopiridinas/química , Aminopiridinas/farmacocinética , Animais , Linhagem Celular , Inibidores das Enzimas do Citocromo P-450 , Inibidores Enzimáticos/farmacologia , Humanos , Indóis/química , Indóis/farmacocinética , Estrutura Molecular , Ratos , Receptor 5-HT2C de Serotonina , Antagonistas da Serotonina/química , Antagonistas da Serotonina/farmacocinéticaRESUMO
SB 242084 has a high affinity (pKi 9.0) for the cloned human 5-HT2C receptor and 100- and 158-fold selectivity over the closely related cloned human 5-HT2B and 5-HT2A subtypes respectively. SB 242084 had over 100-fold selectivity over a range of other 5-HT, dopamine and adrenergic receptors. In studies of 5-HT-stimulated phosphatidylinositol hydrolysis using SH-SY5Y cells stably expressing the cloned human 5-HT2C receptor, SB 242084 acted as an antagonist with a pKb of 9.3, which closely resembled its corresponding receptor binding affinity. SB 242084 potently inhibited m-chlorophenylpiperazine (mCPP, 7 mgkg i.p. 20 min pre-test)-induced hypolocomotion in rats, a model of in vivo central 5-HT2C receptor function, with an ID50 of 0.11 mg/kg i.p., and 2.0 mg/kg p.o. SB 242084 (0.1-1 mg/kg i.p.) exhibited an anxiolytic-like profile in the rat social interaction test, increasing time spent in social interaction, but having no effect on locomotion. SB 242084 (0.1-1 mg/kg i.p.) also markedly increased punished responding in a rat Geller-Seifter conflict test of anxiety, but had no consistent effect on unpunished responding. A large acute dose of SB 242084 (30 mg/kg p.o.) had no effect on seizure susceptibility in the rat maximal electroshock seizure threshold test. Also, while SB 242084 (2 and 6 mg/kg p.o. 1 hr pre-test) antagonized the hypophagic response to mCPP, neither acute nor subchronic administration of the drug, for 5 days at 2 or 6 mg/kg p.o. twice daily, affected food intake or weight gain. The results suggest that SB 242084 is the first reported selective potent and brain penetrant 5-HT2C receptor antagonist and has anxiolytic-like activity, but does not possess either proconvulsant or hyperphagic properties which are characteristic of mutant mice lacking the 5-HT2C receptor.
Assuntos
Aminopiridinas/farmacologia , Encéfalo/metabolismo , Indóis/farmacologia , Receptores de Serotonina/metabolismo , Antagonistas da Serotonina/farmacologia , Aminopiridinas/farmacocinética , Animais , Ansiedade/induzido quimicamente , Ansiedade/psicologia , Conflito Psicológico , Eletrochoque , Comportamento Alimentar/efeitos dos fármacos , Humanos , Indóis/farmacocinética , Masculino , Atividade Motora/efeitos dos fármacos , Fosfatidilinositóis/metabolismo , Piperazinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Serotonina/efeitos dos fármacos , Antagonistas da Serotonina/farmacocinética , Agonistas do Receptor de Serotonina/farmacologia , Comportamento Social , Células Tumorais CultivadasRESUMO
The synthesis and biological activity are reported for a series of analogues of the previously published indole urea 2 (SB-206553), designed to probe the 5-HT(2C) receptor binding site. Small molecule modeling studies have been used to define a region in space which is allowed at the 5-HT(2C) receptor but disallowed at the 5-HT(2A) receptor. In a complementary approach, docking of 2 into our model of the 5-HT(2C) receptor has allowed us to propose a novel primary binding interaction for this series of diaryl ureas, involving a potential double hydrogen-bonding interaction between the urea carbonyl oxygen of the ligand and two serine residues in the receptor. The difference of two valine residues in the 5-HT(2C) receptor for leucine residues in the 5-HT(2A) receptor is believed to account for the observed 5-HT(2C)/5-HT(2A) selectivity with 2.
Assuntos
Antagonistas da Serotonina/síntese química , Animais , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/metabolismo , Técnicas In Vitro , Indóis/química , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Piridinas/química , Ensaio Radioligante , Ratos , Antagonistas da Serotonina/metabolismo , Antagonistas da Serotonina/farmacologiaRESUMO
1. SB 206553 (5-methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo[2 ,3-f]indole) displays a high affinity (pK1 7.9) for the cloned human 5-HT2C receptor expressed in HEK 293 cells and the 5-HT2B receptor (pA2 8.9) as measured in the rat stomach fundus preparation. SB 206553 has low affinity for cloned human 5-HT2A receptors expressed in HEK 293 cells (pK1 5.8) and (pK1 < 6) for a wide variety of other neurotransmitter receptors. 2. SB 206553 appears to be a surmountable antagonist of 5-HT-stimulated phosphoinositide hydrolysis in HEK 293 cells expressing the human 5-HT2C receptor (pKB 9.0). 3. The compound potently (ID50 5.5 mg kg-1, p.o., 0.27 mg kg-1, i.v.) inhibited the hypolocomotor response to m-chlorophenylpiperazine (mCPP), a putative model of 5-HT2C/5-HT2B receptor function in vivo. 4. At similar doses (2-20 mg kg-1, p.o.) SB 206553 increased total interaction scores in a rat social interaction test and increased punished responding in a rat Geller-Seifter conflict test. These effects are consistent with the possession of anxiolytic properties. 5. SB 206553 also increased suppressed responding in a marmoset conflict model of anxiety at somewhat higher doses (15 and 20 mg kg-1, p.o.) but also reduced unsuppressed responding. 6. These results suggest that SB 206553 is a potent mixed 5-HT2C/5-HT2B receptor antagonist with selectivity over the 5-HT2A and all other sites studied and possesses anxiolytic-like properties.
Assuntos
Ansiolíticos/farmacologia , Indóis/farmacologia , Piridinas/farmacologia , Antagonistas da Serotonina/farmacologia , Animais , Callithrix , Linhagem Celular , Conflito Psicológico , Feminino , Humanos , Técnicas In Vitro , Rim/efeitos dos fármacos , Rim/metabolismo , Masculino , Atividade Motora/efeitos dos fármacos , Fosfatidilinositóis/metabolismo , Piperazinas/farmacologia , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Agonistas do Receptor de Serotonina/farmacologia , Comportamento SocialRESUMO
The preparation of a series of conformationally restricted analogues of indolylurea 1, namely tetrahydropyrroloindoles and tetrahydropyrroloquinolines, is described. The binding affinities of these compounds at 5-HT2A, 5-HT2B, and 5-HT2C receptors were determined. Of these compounds, the 1,2,3,5-tetrahydropyrrolo[2,3-f]indole derivative, compound 11, was found to have high affinity for the 5-HT2C (pKI 8.0) and 5-HT2B receptors (pA2 8.5), with excellent selectivity over the 5-HT2A and various other receptors (pKI < 6). 11 is also considerably more active than 1 in both an in vitro functional model, 5-HT-stimulated phosphoinositol hydrolysis (pKB 8.8), and an in vivo functional model, mCPP-induced hypolocomotion (ID50 5.5 mg/kg po). 11 should therefore be of significant utility as a pharmacological tool to delineate the functional significance of blockade of 5-HT2B and 5-HT2C receptors.
Assuntos
Indóis/farmacologia , Piridinas/farmacologia , Antagonistas da Serotonina/farmacologia , Administração Oral , Animais , Indóis/administração & dosagem , Indóis/química , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Piridinas/administração & dosagem , Piridinas/química , Ratos , Receptor 5-HT2B de Serotonina , Receptores de Serotonina , Antagonistas da Serotonina/administração & dosagem , Antagonistas da Serotonina/químicaAssuntos
Indóis/síntese química , Indóis/farmacologia , Receptores de Serotonina/metabolismo , Antagonistas da Serotonina/síntese química , Antagonistas da Serotonina/farmacologia , Ureia/análogos & derivados , Animais , Humanos , Ratos , Ureia/síntese química , Ureia/metabolismo , Ureia/farmacologiaAssuntos
Indóis/síntese química , Antagonistas da Serotonina , Ureia/análogos & derivados , Animais , Sítios de Ligação , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Cobaias , Humanos , Indóis/metabolismo , Indóis/farmacologia , Masculino , Ratos , Ratos Sprague-Dawley , Receptores de Serotonina/metabolismo , Relação Estrutura-Atividade , Ureia/síntese química , Ureia/metabolismo , Ureia/farmacologiaRESUMO
A series of pyrazolo[4,3-c]pyridines has been synthesized and evaluated as potential anxiolytic agents. Selected compounds from this series show a pharmacological profile of action different from that of diazepam. A number of the compounds possess higher affinity for central benzodiazepine receptors than diazepam, yet show less anticonvulsant activity and are less sedative. The structure-activity relationships of these potential anxiolytic agents are discussed.