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1.
J Pharmacol Exp Ther ; 322(1): 172-9, 2007 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17403993

RESUMO

The human histamine H(1) receptor (H(1)R) is a prototypical G protein-coupled receptor and an important, well characterized target for the development of antagonists to treat allergic conditions. Many neuropsychiatric drugs are also known to potently antagonize this receptor, underlying aspects of their side effect profiles. We have used the cell-based receptor selection and amplification technology assay to further define the clinical pharmacology of the human H(1)R by evaluating >130 therapeutic and reference drugs for functional receptor activity. Based on this screen, we have reported on the identification of 8R-lisuride as a potent stereospecific partial H(1)R agonist (Mol Pharmacol 65:538-549, 2004). In contrast, herein we report on a large number of varied clinical and chemical classes of drugs that are active in the central nervous system that display potent H(1)R inverse agonist activity. Absolute and rank order of functional potency of these clinically relevant brain-penetrating drugs may possibly be used to predict aspects of their clinical profiles, including propensity for sedation.


Assuntos
Fármacos do Sistema Nervoso Central/farmacologia , Antagonistas dos Receptores Histamínicos H1/farmacologia , Receptores Histamínicos H1/efeitos dos fármacos , Animais , Células COS , Chlorocebus aethiops , Clonagem Molecular , Agonistas dos Receptores Histamínicos/farmacologia , Humanos , Metilistaminas/farmacologia , Camundongos , Células NIH 3T3 , Pirilamina/farmacologia
2.
J Pharmacol Exp Ther ; 315(3): 1278-87, 2005 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16135699

RESUMO

Drugs that antagonize D2-like receptors are effective antipsychotics, but the debilitating movement disorder side effects associated with these drugs cannot be dissociated from dopamine receptor blockade. The "atypical" antipsychotics have a lower propensity to cause extrapyramidal symptoms (EPS), but the molecular basis for this is not fully understood nor is the impact of inverse agonism upon their clinical properties. Using a cell-based functional assay, we demonstrate that overexpression of Galphao induces constitutive activity in the human D2-like receptors (D2, D3, and D4). A large collection of typical and atypical antipsychotics was profiled for activity at these receptors. Virtually all were D2 and D3 inverse agonists, whereas none was D4 inverse agonist, although many were potent D4 antagonists. The inverse agonist activity of haloperidol at D2 and D3 receptors could be reversed by mesoridazine demonstrating that there were significant differences in the degrees of inverse agonism among the compounds tested. Aripiprazole and the principle active metabolite of clozapine NDMC [8-chloro-11-(1-piperazinyl)-5H-dibenzo [b,e] [1,4] diazepine] were identified as partial agonists at D2 and D3 receptors, although clozapine itself was an inverse agonist at these receptors. NDMC-induced functional responses could be reversed by clozapine. It is proposed that the low incidence of EPS associated with clozapine and aripiprazole used may be due, in part, to these partial agonist properties of NDMC and aripiprazole and that bypassing clozapine blockade through direct administration of NDMC to patients may provide superior antipsychotic efficacy.


Assuntos
Antipsicóticos/metabolismo , Clozapina/metabolismo , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D3/agonistas , Receptores de Dopamina D4/metabolismo , Animais , Haloperidol/farmacologia , Humanos , Camundongos , Células NIH 3T3 , Pergolida/farmacologia , Plasmídeos , Proteínas RGS/metabolismo , Transfecção
3.
Psychopharmacology (Berl) ; 177(1-2): 207-16, 2004 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-15258717

RESUMO

RATIONALE: Clozapine is a unique antipsychotic, with efficacy against positive symptoms in treatment-resistant schizophrenic patients, and the ability to improve cognition and treat the negative symptoms characteristic of this disease. Despite its unique clinical actions, no specific molecular mechanism responsible for these actions has yet been described. OBJECTIVES AND METHODS: To comprehensively profile a large library of neuropsychiatric drugs, including most antipsychotics, at human monoamine receptors using R-SAT, an in vitro functional assay. RESULTS: Profiling revealed that N-desmethylclozapine (NDMC), the principal metabolite of clozapine, but not clozapine itself, is a potent and efficacious muscarinic receptor agonist, a molecular property not shared by any other antipsychotic. To further explore the role of NDMC muscarinic receptor agonist properties in mediating the physiological actions of clozapine, systemically administered NDMC was found to stimulate the phosphorylation of mitogen-activated protein kinase (MAP kinase) in mouse CA1 hippocampal neurons, an effect that was blocked by scopolamine, confirming central M1 muscarinic receptor agonist activity in vivo. Lastly, an analysis of clozapine and NDMC serum levels in schizophrenic patients indicated that high NDMC/clozapine ratios better predicted improvement in cognitive functioning and quality of life than the levels of either compound alone. CONCLUSIONS: The muscarinic receptor agonist activities of NDMC are unique among antipsychotics, and provide a possible molecular basis for the superior clinical effects of clozapine pharmacotherapy.


Assuntos
Clozapina/análogos & derivados , Clozapina/farmacologia , Agonistas Muscarínicos/farmacologia , Receptor Muscarínico M1/agonistas , Animais , Células CHO , Cricetinae , Relação Dose-Resposta a Droga , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Células NIH 3T3 , Receptor Muscarínico M1/fisiologia
4.
Mol Pharmacol ; 65(3): 538-49, 2004 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-14978232

RESUMO

The human histamine H1 receptor (H1R) is an important, well characterized target for the development of antagonists to treat allergic conditions. Many neuropsychiatric drugs are known to potently antagonize the H1R, thereby producing some of their side effects. In contrast, the tolerability and potential therapeutic utility of H1R agonism is currently unclear. We have used a cell-based functional assay to evaluate known therapeutics and reference drugs for H1R agonist activity. Our initial functional screen identified three ergot-based compounds possessing heretofore-unknown H1R agonist activity. 8R-lisuride demonstrated potent agonist activity in various assays including receptor selection and amplification technology, inositol phosphate accumulation, and activation of nuclear factor-kappaB with pEC50 values of 8.1, 7.9, and 7.9, respectively, and with varying degrees of efficacy. Based on these assays, 8R-lisuride is the most potent stereospecific partial agonist for the human H1R yet reported. Investigation of the residues involved in histamine and lisuride binding, using H1R mutants and molecular modeling, have revealed that although these ligands are structurally different, the lisuride-binding pocket in the H1R closely corresponds to the histamine-binding pocket. The discovery of a potent stereospecific partial H1R agonist provides a valuable tool to further characterize this important therapeutic target in vitro.


Assuntos
Agonistas dos Receptores Histamínicos/farmacologia , Lisurida/farmacologia , Receptores Histamínicos H1/metabolismo , Células 3T3 , Animais , Sítios de Ligação , Clonagem Molecular , Análise Mutacional de DNA , Ergolinas/farmacologia , Células HeLa , Humanos , Lisurida/química , Camundongos , Modelos Moleculares , Conformação Molecular , Agonistas do Receptor de Serotonina/farmacologia
5.
J Pharmacol Exp Ther ; 299(1): 268-76, 2001 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-11561089

RESUMO

We have used a cell-based functional assay to define the pharmacological profiles of a wide range of central nervous system active compounds as agonists, competitive antagonists, and inverse agonists at almost all known monoaminergic G-protein-coupled receptor (GPCR) subtypes. Detailed profiling of 40 antipsychotics confirmed that as expected, most of these agents are potent competitive antagonists of the dopamine D2 receptor. Surprisingly, this analysis also revealed that most are potent and fully efficacious 5-hydroxytryptamine (5-HT)2A receptor inverse agonists. No other molecular property was shared as universally by this class of compounds. Furthermore, comparisons of receptor potencies revealed that antipsychotics with the highest extrapyramidal side effects (EPS) liability are significantly more potent at D2 receptors, the EPS-sparing atypical agents had relatively higher potencies at 5-HT2A receptors, while three were significantly more potent at 5-HT2A receptors. Functional high-throughput screening of a diverse chemical library identified 530 ligands with inverse agonist activity at 5-HT2A receptors, including several series of compounds related to known antipsychotics, as well as a number of novel chemistries. An analog of one of the novel chemical series, AC-90179, was pharmacologically profiled against the remaining monoaminergic GPCRs and found to be a highly selective 5-HT2A receptor inverse agonist. The behavioral pharmacology of AC-90179 is characteristic of an atypical antipsychotic agent.


Assuntos
Antipsicóticos/farmacologia , Receptores de Serotonina/efeitos dos fármacos , Agonistas do Receptor de Serotonina/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Clonagem Molecular , Avaliação Pré-Clínica de Medicamentos , Proteínas de Ligação ao GTP/metabolismo , Amplificação de Genes , Movimentos da Cabeça/efeitos dos fármacos , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Relação Quantitativa Estrutura-Atividade , Ratos , Ratos Sprague-Dawley , Receptor 5-HT2A de Serotonina , Reflexo de Sobressalto/efeitos dos fármacos
7.
Pharmacol Toxicol ; 86(1): 44-50, 2000 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-10720106

RESUMO

The interaction of (R) and (S) enantiomers of the chiral oxotremorine analogue BM-5 with muscarinic acetylcholine receptors was studied in vitro using radioligand binding and isolated tissue preparations. The in vivo effects of (R)-BM-5 were also studied in anaesthetised cat. No receptor or tissue selectivity was found for either enantiomer in radioligand binding studies in cells expressing human muscarinic receptors (M1-M5) or in guinea pig tissues. The affinity of (R)-BM-5 was about 40 times, or 15-60 times higher than that of (S)-BM-5 in recombinant cells or in guinea pig tissues, respectively. Both enantiomers induced contraction of the guinea pig isolated urinary bladder and ileum. (R)-BM-5 was more potent than (S)-BM-5 in bladder (EC50 590 and 3500 nM, respectively) and in ileum (EC50 39 and 2600 nM, respectively). The maximal agonist effect was lower for (R)-BM-5 than for (S)-BM-5 in bladder (2.7% and 6.6%, respectively) and in ileum (32% and 48%, respectively). Contractions were completely inhibited by atropine (1 microM). In vivo, (R)-BM-5 induced bladder contraction and salivation after intravenous administration in the anaesthetised cat (ED50 4.1 and 6.2 microg kg(-1), respectively). In conclusion, (R)- and (S)-BM-5 act as partial muscarinic agonists in the isolated bladder and ileum. (R)-BM-5 was the more potent enantiomer but had a lower maximal agonist effect giving an opposed enantioselectivity for affinity and efficacy. (R)-BM-5 showed agonist activity in vivo, confirming in vitro findings. From affinity and efficacy data it can be concluded that the effects of racemic BM-5 are mediated by the (R)-enantiomer.


Assuntos
Agonistas Muscarínicos/farmacologia , Pirrolidinas/farmacologia , Animais , Ligação Competitiva , Células CHO , Gatos , Cricetinae , Relação Dose-Resposta a Droga , Cobaias , Humanos , Íleo/efeitos dos fármacos , Íleo/metabolismo , Íleo/fisiologia , Técnicas In Vitro , Cinética , Masculino , Agonistas Muscarínicos/metabolismo , Antagonistas Muscarínicos/farmacologia , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , Parassimpatomiméticos/metabolismo , Parassimpatomiméticos/farmacologia , Pirrolidinas/metabolismo , Quinuclidinil Benzilato/antagonistas & inibidores , Quinuclidinil Benzilato/metabolismo , Quinuclidinil Benzilato/farmacologia , Ensaio Radioligante , Receptores Muscarínicos/classificação , Receptores Muscarínicos/metabolismo , Estereoisomerismo , Trítio , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/metabolismo , Bexiga Urinária/fisiologia
10.
J Med Chem ; 43(7): 1339-49, 2000 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-10753471

RESUMO

The design and synthesis of a well-characterized novel ring system, (R)-lambda1,11-methyleneaporphine [(R)-4], and 15 derivatives thereof are presented. The addition of various nucleophiles to (R)-lambda1,11-carbonylaporphine [(R)-11] or to the 1,11-hydroxymethyleneaporphine epimers gave separable mixtures of epimers. The epimeric ratios obtained in most reactions seem to be a result of steric factors directing the nucleophilic attack. The structure of the epimers was determined by a combination of X-ray crystallography (5 derivatives), NMR spectroscopy, and chemical correlation. Interesting and diverse pharmacological profiles of the derivatives were revealed through binding studies at serotonin 5-HT(7) and 5-HT(1A) receptors as well as at dopamine D(2A) receptors. Two derivatives appeared to be selective 5-HT(7) receptor antagonists. It is evident from our results that the novel ring system [(R)-4] provides a useful complement to other scaffolds available to medicinal chemists involved in studies of GPC receptors.


Assuntos
Aporfinas/síntese química , Proteínas de Ligação ao GTP/metabolismo , Receptores de Dopamina D2/metabolismo , Receptores de Serotonina/metabolismo , Animais , Aporfinas/química , Aporfinas/metabolismo , Ligação Competitiva , Células CHO , Cricetinae , Cristalografia por Raios X , Hipocampo/metabolismo , Humanos , Técnicas In Vitro , Espectroscopia de Ressonância Magnética , Conformação Molecular , Ensaio Radioligante , Ratos , Receptores 5-HT1 de Serotonina , Estereoisomerismo
11.
Bioorg Med Chem Lett ; 9(11): 1583-6, 1999 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-10386940

RESUMO

Novel 8-aryl and 8-aroyl substituted derivatives of 3-(dipropylamino)chroman are described. The compounds have been prepared by a palladium catalyzed reaction of iodoarenes and a stannylated derivative of [eta6-3-(dipropylamino)chroman]Cr(CO)3. Several of the compounds have high affinity for 5-HT1A receptors whereas the affinity for D2A receptors is lower, the 8-arylated derivatives being slightly more potent than the 8-aroylated analogues.


Assuntos
Cromanos/síntese química , Receptores de Dopamina D2/agonistas , Agonistas do Receptor de Serotonina/metabolismo , Animais , Encéfalo/metabolismo , Fibroblastos , Humanos , Camundongos , Modelos Químicos , Ratos , Relação Estrutura-Atividade
12.
J Med Chem ; 42(7): 1115-22, 1999 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-10197956

RESUMO

Various approaches to the synthesis of all four stereoisomers of 2-(1H-imidazol-4-yl)cyclopropylamine (cyclopropylhistamine) are described. The rapid and convenient synthesis and resolution of trans-cyclopropylhistamine is reported. The absolute configuration of its enantiomers was determined by single-crystal X-ray crystallographic analysis. The distinct trans-cyclopropylhistamine enantiomers were tested for their activity and affinity on the histamine H3 receptor. (1S,2S)-Cyclopropylhistamine (VUF 5297) acts as an agonist both on the rat cortex (pD2 = 7.1; alpha = 0.75) and on guinea pig jejunum (pD2 = 6.6; alpha = 0.75). Its enantiomer, (1R, 2R)-cyclopropylhistamine (VUF 5296), is about 1 order of magnitude less active. Both enantiomers show weak activity on H1 and H2 receptors. All synthetic attempts to cis-cyclopropylhistamine were unsuccessful. Nevertheless, the results of this study provide an ideal template for molecular modeling studies of histamine H3 receptor ligands.


Assuntos
Ciclopropanos/síntese química , Histamina/análogos & derivados , Receptores Histamínicos H3/metabolismo , Animais , Sítios de Ligação , Ligação Competitiva , Córtex Cerebral/metabolismo , Cristalografia por Raios X , Ciclopropanos/química , Ciclopropanos/metabolismo , Ciclopropanos/farmacologia , Cobaias , Frequência Cardíaca/efeitos dos fármacos , Histamina/síntese química , Histamina/química , Histamina/metabolismo , Histamina/farmacologia , Agonistas dos Receptores Histamínicos/síntese química , Agonistas dos Receptores Histamínicos/química , Agonistas dos Receptores Histamínicos/metabolismo , Agonistas dos Receptores Histamínicos/farmacologia , Íleo/efeitos dos fármacos , Íleo/fisiologia , Técnicas In Vitro , Jejuno/efeitos dos fármacos , Jejuno/fisiologia , Modelos Moleculares , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , Norepinefrina/metabolismo , Ratos , Receptores Histamínicos H1/efeitos dos fármacos , Receptores Histamínicos H2/efeitos dos fármacos , Estereoisomerismo , Relação Estrutura-Atividade
13.
Methods Mol Med ; 23: 1-23, 1999.
Artigo em Inglês | MEDLINE | ID: mdl-21380888

RESUMO

This chapter focuses on the isosteric replacement of peptide bonds with three different types of heterocyclic ring systems (1); 1,2,4-oxadiazole (2), 1,3,4-oxadiazole (3), and 1,2,4-triazole rings (4-6). The ring systems are similar in size and shape but show variations in aromatic, electrostatic, and hydrogen bonding properties. These variations provide opportunities to study properties of importance for amide bond mimicry. The derivatives are synthesized from protected natural amino acids, and the reaction conditions have been chosen so that the enantiopurity is retained during the reaction sequences. Two series of mimetics will be described, one in which the carboxylic acid functionality is directly attached to the heterocyclic ring (1) and one series with a methylene group inserted between the ring and the carboxylic acid group (7). Since we have focused on the design and synthesis of Phe-Gly mimetics, the synthetic examples described here start from L: -phenylalanine. However, we have used the same synthetic scheme also for other amino acids and notes will be given when other derivatives require differences in reaction conditions (1). The use of the dipeptidomimetics as building blocks in pseudopeptide synthesis will also be described (7). These syntheses are performed on solid phase using Boc-chemistry. Also, the deprotection and purification of the pseudopeptides by reversed phase HPLC will be discussed.

14.
Chirality ; 10(9): 813-20, 1998.
Artigo em Inglês | MEDLINE | ID: mdl-9839431

RESUMO

The four stereoisomers of the antimuscarinic 3-(2,3-dihydrobenzofuran-2-yl)quinuclidine have been prepared by a method involving chromatographic separation of the racemic diastereoisomers as borane complexes. The relative and absolute configurations of the stereoisomers were determined by X-ray crystallographic methods. The crystal structure of (2'R,3R)-3-(2,3-dihydrobenzofuran-2-yl)quinuclidine.HCl.H2O contains two independent molecules with different conformations of both the quinuclidine moiety and the dihydrofuran ring.


Assuntos
Antagonistas Muscarínicos/química , Quinuclidinas/química , Receptores Muscarínicos/metabolismo , Animais , Cristalografia por Raios X , Cobaias , Antagonistas Muscarínicos/metabolismo , Quinuclidinas/metabolismo , Estereoisomerismo
15.
Eur J Pharmacol ; 346(2-3): 299-307, 1998 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-9652373

RESUMO

The affinities of 19 pharmacologically diverse dopamine D2 receptor ligands were determined for the active and inactive conformations of cloned human dopamine D2 receptors expressed in Ltk cells. The agonist [3H]quinpirole was used to selectively label the guanine nucleotide-binding protein-coupled, active receptor conformation. The antagonist [3H]raclopride, in the presence of the non-hydrolysable GTP-analogue Gpp(NH)p and sodium ions and in the absence of magnesium ions, was used to label the free inactive receptor conformation. The intrinsic activities of the ligands were determined in a forskolin-stimulated cyclic AMP assay using the same cells. An excellent correlation was shown between the affinity ratios (KR/KRG) of the ligands for the two receptor conformations and their intrinsic activity (r=0.96). The ligands included eight structurally related and enantiopure 2-aminotetralin derivatives; the enantiomers of 5-hydroxy-2-(dipropylamino)tetralin, 5-methoxy-2-(dipropylamino)tetralin, 5-fluoro-2-(dipropylamino)tetralin and 2-(dipropylamino)tetralin. The (S)-enantiomers behaved as full agonists in the cyclic AMP assay and displayed a large KR/KRG ratio. The (R)-enantiomers were classified as partial agonists and had lower ratios. The structure-affinity relationships of these compounds at the active and the inactive receptor conformations were analysed separately, and used in conjunction with a homology based receptor model of the dopamine D2 receptor. This led to proposed binding modes for agonists, antagonists and partial agonists in the 2-aminotetralin series. The concepts used in this study should be of value in the design of ligands with predetermined affinity and intrinsic activity.


Assuntos
Receptores de Dopamina D2/efeitos dos fármacos , Células Cultivadas , Clonagem Molecular , Colforsina/farmacologia , AMP Cíclico/biossíntese , Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/farmacologia , Humanos , Ligantes , Conformação Proteica , Quimpirol/farmacologia , Racloprida , Receptores de Dopamina D2/química , Salicilamidas/farmacologia , Relação Estrutura-Atividade
16.
J Med Chem ; 40(23): 3804-19, 1997 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-9371246

RESUMO

A series of 25 derivatives of the muscarinic antagonist 3-(2-furanyl)quinuclidin-2-ene (4) was synthesized and evaluated for muscarinic and antimuscarinic properties. Substitution at all three positions of the furan ring has been investigated. The affinities of the new compounds were determined by competition experiments in homogenates of cerebral cortex, heart, parotid gland, and urinary bladder from guinea pigs using (-)-[3H]-3-quinuclidinyl benzilate as the radioligand, and the antimuscarinic potency was determined in a functional assay on isolated guinea pig urinary bladder using carbachol as the agonist. Several of the novel derivatives displayed high muscarinic affinities. Whereas the affinity of lead compound 4 for cortical muscarinic receptors is moderate (Ki = 300 nM), it is much higher for the 5-methyl (48; Ki = 12 nM), 5-ethyl (52; Ki = 7.4 nM), 5-bromo (33; Ki = 6.4 nM), and 3-phenyl (49; Ki = 2.8 nM) substituted derivatives. The substituent-induced increases in affinity do not appear to be additive as a 5-bromo-3-phenyl (54), and a 5-methyl-3-phenyl (55) substitution pattern only slightly increases affinity (Ki = 1.55 and 2.39 nM, respectively). The conformational preferences of the 3-phenyl (49) and 5-phenyl (51) derivatives were studied by X-ray crystallography and molecular mechanics calculations. Because of the observed high affinity of 49, a series of 16 meta- and para-substituted analogues of 49 was synthesized and tested. The m-hydroxy derivative (68) exhibited more than 10-fold improvement in affinity as compared to 49. The structure-activity relationships of the new series are well described with QSAR and CoMFA models.


Assuntos
Antagonistas Muscarínicos/síntese química , Antagonistas Muscarínicos/farmacologia , Quinuclidinas/síntese química , Quinuclidinas/farmacologia , Animais , Ligação Competitiva , Córtex Cerebral/ultraestrutura , Cobaias , Técnicas In Vitro , Cinética , Masculino , Conformação Molecular , Antagonistas Muscarínicos/metabolismo , Músculo Liso/efeitos dos fármacos , Miocárdio/ultraestrutura , Glândula Parótida/ultraestrutura , Quinuclidinas/metabolismo , Quinuclidinil Benzilato/metabolismo , Ensaio Radioligante , Receptores Muscarínicos/metabolismo , Relação Estrutura-Atividade , Trítio , Bexiga Urinária/ultraestrutura
18.
J Chem Inf Comput Sci ; 37(4): 812-8, 1997.
Artigo em Inglês | MEDLINE | ID: mdl-9254913

RESUMO

Explicit molecular binding pockets were constructed and optimized around sets of superimposed ligands using the minireceptor concept. The resulting binding sites incorporate the properties of the different ligands and were shown to be suitable for the design of molecules presenting novel interaction patterns. Two applications of minireceptor construction and/or optimization, followed by molecular design are described. In the pursuit of new ligands mimicking the action of paclitaxel, a minireceptor was constructed using the primary amino acid sequence of the target protein as a guide. The active site extracted from a homology-based model of the serotonin 5-HT1A receptor was optimized around a set of three ligands using the same approach.


Assuntos
Desenho de Fármacos , Receptores de Superfície Celular/metabolismo , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Sítios de Ligação , Ligantes , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Paclitaxel/química , Paclitaxel/farmacologia , Conformação Proteica , Receptores de Superfície Celular/química , Receptores de Serotonina/química , Receptores de Serotonina/metabolismo , Receptores 5-HT1 de Serotonina
19.
J Pharm Pharmacol ; 49(2): 169-77, 1997 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-9055190

RESUMO

R- and S-8-(2-Furyl)- and R- and S-8-phenyl-2-(di-n-propylamino)tetralins (R- and S-LY-55 and R- and S-LY-49, respectively), novel enantiopure dipropylaminotetralins, have been screened as 5-HT1A receptor ligands. All had nanomolar affinities for 5-HT1A receptors and fully inhibited forskolin-stimulated adenylyl cyclase in-vitro (i.e. the four compounds appeared to be 5-HT1A agonists). It was also found that the enantiomers of LY-55 behaved as typical 5-HT1A receptor agonists in rats in-vivo by inducing a typical behavioural 5-HT syndrome, hypothermia and a decrease in 5-HT synthesis and turnover, indicating effects both on postsynaptic 5-HT1A receptors and somatodendritic 5-HT1A autoreceptors. In contrast, R- and S-LY-49 did not cause any 5-HT1A receptor-related effects in-vivo except for a partial inhibition of 5-HT synthesis after high doses. The 5-HT1A receptor antagonist WAY-100635 was shown to attenuate the R-LY-49-induced inhibition of 5-HT synthesis, indicating the compound to be a weak agonist at somatodendritic 5-HT1A autoreceptors. R-LY-49 at a high dose and with a long pre-treatment time interval inhibited the hypothermic and behavioural effects, but not the inhibition of 5-HT synthesis induced by the 5-HT1A receptor agonist R-8-hydroxy-(dipropylamino)tetralin (R-8-OH-DPAT). Taken together, these findings seem to indicate, that R-LY-49 is a weak partial agonist at 5-HT1A receptors. A comparative pharmacokinetic study showed that the enantiomers of LY-55 entered the brain rapidly after subcutaneous administration and reached peak brain tissue/plasma concentration ratios within 15-30 min of injection, whereas the brain concentrations of R-LY-49 increased slowly, reaching a relatively low peak brain tissue/plasma concentration ratio 90 min after injection despite their similar lipophilicity. The differences between the pharmacological activity of the two compounds in-vivo seem to be explained by their different abilities to cross the blood-brain barrier, and a weak agonistic activity of R-LY-49 on 5-HT1A receptors, both pre- and postsynaptically, compared with S-LY-55. Further studies are, however, needed for a deeper understanding of these differences.


Assuntos
Antígenos Ly , Receptores de Serotonina/efeitos dos fármacos , Agonistas do Receptor de Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacocinética , Tetra-Hidronaftalenos/farmacocinética , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Lectinas Tipo C , Masculino , Ratos , Ratos Sprague-Dawley , Receptores Semelhantes a Lectina de Células NK , Receptores de Serotonina/metabolismo , Receptores 5-HT1 de Serotonina , Serotonina/metabolismo , Estereoisomerismo , Comportamento Estereotipado , Tetra-Hidronaftalenos/metabolismo
20.
Int J Pept Protein Res ; 48(4): 337-46, 1996 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-8919054

RESUMO

Nine low molecular weight nerve growth factor (NGF)-like peptides have been designed to mimic the putative receptor-binding epitope of NGF defined by two beta-hairpin loops. Eight different spacers were used as variable links between the beta-loop amino acid residues, which from mutagenesis experiments were found to play an important role in the biological activity of NGF. These spacers were amino acids, natural or non-natural, differing in length (5-13 A) and polarity. The peptides were synthesized via the Fmoc solid-phase peptide synthesis and purified by reversed-phase HPLC. Their primary sequences were analyzed by a combination of automated Edman degradation and mass spectrometry. The peptides were tested using two different biological assays, the fibre outgrowth from chick embryonic sympathetic ganglia and the PC12 cell differentiation assay. Weak antagonistic effects could be observed for some peptides.


Assuntos
Medula Suprarrenal/fisiologia , Gânglios Simpáticos/fisiologia , Fatores de Crescimento Neural/química , Peptídeos/química , Peptídeos/metabolismo , Sequência de Aminoácidos , Animais , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/fisiologia , Embrião de Galinha , Cromatografia Líquida de Alta Pressão , Cristalografia por Raios X , Microscopia , Dados de Sequência Molecular , Fatores de Crescimento Neural/metabolismo , Neuritos/efeitos dos fármacos , Neuritos/fisiologia , Células PC12 , Peptídeos/isolamento & purificação , Ratos , Solubilidade , Espectrometria de Massa de Íon Secundário
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