RESUMO
Phosphodiesterase type 5 (PDE5) inhibitors with improved PDE isozyme selectivity relative to sildenafil may result in agents for the treatment of male erectile dysfunction (MED) with a lower incidence of PDE-associated adverse effects. This paper describes the discovery of 14, a PDE5 inhibitor with improved potency and selectivity in vitro compared to sildenafil. This compound shows activity in a functional assay of erectile function comparable to that of sildenafil.
Assuntos
3',5'-GMP Cíclico Fosfodiesterases/antagonistas & inibidores , Disfunção Erétil/tratamento farmacológico , Imidazóis/síntese química , Pênis/efeitos dos fármacos , Inibidores de Fosfodiesterase/síntese química , Quinazolinas/síntese química , Animais , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5 , Imidazóis/química , Imidazóis/farmacologia , Técnicas In Vitro , Masculino , Pênis/fisiologia , Inibidores de Fosfodiesterase/química , Inibidores de Fosfodiesterase/farmacologia , Piperazinas/farmacologia , Purinas , Purinonas/química , Quinazolinas/química , Quinazolinas/farmacologia , Coelhos , Citrato de Sildenafila , Relação Estrutura-Atividade , SulfonasRESUMO
A series of rotationally restricted phenolic analogs of the neurotransmitter serotonin has been synthesized with the 5-hydroxyindole portion of serotonin replaced by a dihydropyrano[3,2-e]-indole (1, 3, 4, and 5) and a dihydropyrano[2,3-f]indole (2). The receptor binding profile of these compounds has been studied and compared to the natural substrate serotonin. The dihydropyrano[3,2-e]indole derivatives (1, 3, 4, and 5) possess lower affinity for 5-HT1 receptors but equal or greater affinity for 5-HT2 receptors. Like serotonin, these compounds dose-dependently stimulated phosphatidylinositol turnover in rat brain slices. Moreover, the response to 1-(2-aminoethyl)-3-methyl-8,9-dihydropyrano[3,2-]indole (5, CP-132,484) and 1-(2-aminoethyl)-8,9-dihydropyrano[3,2-e]indole (4) is selectively antagonized by 5-HT2 receptor antagonists establishing these tryptamines as selective 5-HT2 receptor agonists. The high affinity and potency of 5 for 5-HT2 receptors suggests that the C5-hydroxy group in serotonin can function as a hydrogen bond acceptor in a 5-HT2 receptor with a directionality of interaction which is down and away from C6 in serotonin (Figure 5). Furthermore, the potent affinity of these compounds for 5-HT2 receptors coupled with their poor affinity for 5-HT1 receptors indicates that the aminoethyl side chain of serotonin adopts significantly different conformations in 5-HT1 versus 5-HT2 receptors.
Assuntos
Indóis/síntese química , Agonistas do Receptor de Serotonina/síntese química , Serotonina/análogos & derivados , Animais , Indóis/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Pirróis/síntese química , Pirróis/farmacologia , Ratos , Receptores de Serotonina/efeitos dos fármacos , Receptores de Serotonina/metabolismo , Agonistas do Receptor de Serotonina/farmacologia , Relação Estrutura-AtividadeRESUMO
A previous report from these laboratories identified the N-3-benzylimidazoquinazolinone nucleus as a more selective PDE5 inhibitor template compared to the pyrazolopyrimidine of sildenafil. This paper describes in detail the structure-activity relationships of a set of sulfonamide analogues, several of which are both more potent and more selective PDE5 inhibitors in vitro than sildenafil. The synthesis, in vitro enzyme activity and selectivity, and in vitro functional and preclinical pharmacokinetic assessment of molecules in this series are described.
Assuntos
Inibidores de Fosfodiesterase/síntese química , Diester Fosfórico Hidrolases/metabolismo , Quinazolinas/síntese química , 3',5'-GMP Cíclico Fosfodiesterases , Animais , Bovinos , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5 , Cães , Avaliação Pré-Clínica de Medicamentos , Humanos , Técnicas In Vitro , Masculino , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , Músculos , Pênis/efeitos dos fármacos , Pênis/fisiologia , Inibidores de Fosfodiesterase/química , Inibidores de Fosfodiesterase/farmacocinética , Inibidores de Fosfodiesterase/farmacologia , Quinazolinas/química , Quinazolinas/farmacocinética , Quinazolinas/farmacologia , Coelhos , Ratos , Relação Estrutura-AtividadeRESUMO
The synthesis and in vitro and in vivo characteristics of 3-(1,2,5,6-tetrahydropyrid-4-yl)pyrrolo[3,2-b]pyrid-5-one (1, CP-93,129) are described. This rotationally restricted phenolic analogue of RU-24,969 is a potent (15 nM) and selective (200x vs the 5-HT1A receptor, 150x vs the 5HT1D receptor) functional agonist for the 5-HT1B receptor. Direct infusion of 1 into the paraventricular nucleus of the hypothalamus of rats significantly inhibits food intake, implicating the role of 5-HT1B receptors in regulating feeding behavior in rodents. 3-(1,2,5,6-Tetrahydropyrid-4-yl)pyrrolo[3,2-b]pyrid-5-one (1) has also been shown to be biochemically discriminatory in its ability to selectively inhibit forskolin-stimulated adenylate cyclase activity only at the 5-HT1B receptor. The source of the selectivity of 1 appears to lie in the ability of a pyrrolo[3,2-b]pyrid-5-one to act as a rotationally restricted bioisosteric replacement for 5-hydroxyindole.
Assuntos
Indóis/farmacologia , Piridinas/farmacologia , Pirróis/farmacologia , Serotonina/fisiologia , Inibidores de Adenilil Ciclases , Animais , Fenômenos Químicos , Química , Colforsina/farmacologia , Ciclização , Ingestão de Alimentos/efeitos dos fármacos , Cobaias , Hipocampo/enzimologia , Estrutura Molecular , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Núcleo Hipotalâmico Paraventricular/fisiologia , Piridinas/síntese química , Piridinas/metabolismo , Pirróis/síntese química , Pirróis/metabolismo , Ratos , Receptores de Serotonina/efeitos dos fármacos , Receptores de Serotonina/fisiologia , Serotonina/farmacologia , Substância Negra/metabolismoRESUMO
Neuronal nicotinic acetylcholine receptors are members of the ligand-gated ion channel receptor superfamily and may play important roles in modulating neurotransmission, cognition, sensory gating, and anxiety. Because of its distribution and abundance in the CNS, the alpha 7 nicotinic receptor is a strong candidate to be involved in some of these functions. In this paper we describe the synthesis and in vitro profile of AR-R17779, (-)-spiro[1-azabicyclo[2.2. 2]octane-3,5'-oxazolidin-2'-one] (4a), a potent full agonist at the rat alpha 7 nicotinic receptor, which is highly selective for the rat alpha 7 nicotinic receptor over the alpha 4 beta 2 subtype. Preliminary SAR of AR-R17779 presented here indicate that there is little scope for modification of this rigid molecule as even minor changes result in significant loss of the alpha 7 nicotinic receptor affinity.
Assuntos
Acetilcolina/química , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Agonistas Nicotínicos/farmacologia , Receptores Nicotínicos/efeitos dos fármacos , Compostos de Espiro/farmacologia , Animais , Hidrocarbonetos Aromáticos com Pontes/síntese química , Hidrocarbonetos Aromáticos com Pontes/metabolismo , Hipocampo/metabolismo , Técnicas In Vitro , Agonistas Nicotínicos/síntese química , Agonistas Nicotínicos/metabolismo , Oócitos/metabolismo , Oócitos/fisiologia , Prosencéfalo/metabolismo , Ensaio Radioligante , Ratos , Receptores Nicotínicos/metabolismo , Compostos de Espiro/síntese química , Compostos de Espiro/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade , Xenopus , Receptor Nicotínico de Acetilcolina alfa7RESUMO
1. The aim of the present study was to investigate the in vivo pharmacological profile of CP-122,288, an indole-derivative with a conformationally restricted N-methylpyrrolidinyl basic side chain in the C-3 position. This C-3 substituent structurally differentiates CP-122,288 from the 5-HT1D receptor agonist sumatriptan, which possesses an N,N-dimethylaminoethyl group. [Formula: see text] 2. When administered prior to electrical stimulation of the trigeminal ganglion, CP-122,288 (0.3-300 ng kg-1, i.v.) produced a dose-related inhibition of plasma protein extravasation in rat dura mater (minimum effective dose, MED, 3 ng kg-1 i.v., P < 0.05; maximal inhibition of plasma extravasation at 30 ng kg-1 i.v., P < 0.01). Sumatriptan produced a similar inhibition of plasma leakage in the dura, but at much higher dose levels (MED, 100 micrograms kg-1 i.v., P < 0.05). Thus, CP-122,288 is of the order of 10(4) fold more potent than sumatriptan. 3. At all doses tested, CP-122,288 did not inhibit plasma protein extravasation measured in extracranial tissues such as the lower lip, eyelid, and conjunctiva. 4. In a separate series of studies in the anaesthetized rat, CP-122,288 (0.003-3 micrograms kg-1 i.v.) produced no change in either heart rate or mean arterial blood pressure, thus demonstrating that doses of CP-122,288 which inhibit plasma protein leakage in rat dura, are devoid of hemodynamic effects. 5. Following a 5 min period of electrical stimulation of the trigeminal ganglion, a 20 min period of sustained neurogenically-driven plasma extravasation, occurring in the absence of electrical stimulation, was initiated. By administration of the compound 5 min after completing the phase of electrical stimulation, this protocol permitted the evaluation of the activity of CP-122,288 on an ongoing and established inflammatory event. CP-122,288 (30 and 300 ng kg-1, i.v., P < 0.01 and P < 0.05, respectively) produced a complete inhibition of plasma protein leakage which was consistent with its effects when administered prior to trigeminal ganglion stimulation. 6. In the anaesthetized dog, CP-122,288 and sumatriptan, at 1-300 micrograms kg-1, i.v., produced a dose-dependent reduction in carotid arterial blood flow and coronary arterial diameter. These data demonstrate that sumatriptan inhibits neurogenic inflammation in the rat (MED, 100 micrograms kg-1, i.v.), and produces vasoconstriction in the dog, over a similar dose-range. Interestingly, doses of CP-122,288 that inhibit neurogenic inflammation in rat dura mater (0.3-300 ng kg-1) were demonstrated to be devoid of vasoconstrictor activity in either the carotid or coronary vascular beds of dog. 7. These data demonstrate that in the rat, CP-122,288 is a highly potent and selective inhibitor of neurogenic inflammation in intracranial tissues, at doses which are devoid of vasoconstrictor activity in dog. Potentially, CP-122,288 may be of use for the acute treatment of migraine, without the risk of cardiovascular side-effects.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Inflamação/tratamento farmacológico , Pirrolidinas/farmacologia , Agonistas do Receptor de Serotonina/farmacologia , Sumatriptana/análogos & derivados , Anestesia , Animais , Permeabilidade Capilar/efeitos dos fármacos , Cães , Relação Dose-Resposta a Droga , Dura-Máter/efeitos dos fármacos , Dura-Máter/metabolismo , Estimulação Elétrica , Hemodinâmica/efeitos dos fármacos , Inflamação/fisiopatologia , Masculino , Ratos , Ratos Sprague-Dawley , Especificidade da Espécie , Sumatriptana/farmacologia , Gânglio Trigeminal/efeitos dos fármacos , Gânglio Trigeminal/fisiologia , Vasoconstrição/efeitos dos fármacosRESUMO
CP-135,807 [3-(N-methylpyrrolidin-2R-ylmethyl)-5-(3-nitropyrid-2- yl)amino-1H-indole] binds with high affinity to central 5-HT1D receptors, and in functional studies produces dose-dependent decreases in extracellular serotonin. These and other findings have suggested that CP-135,807 may act as a terminal 5-HT autoreceptor agonist. In an attempt to characterize the behavioral activity of selective 5-HT1D ligands, adult male Carneau pigeons were trained to discriminate IM injections of 0.1 mg/kg CP-135,807 from saline under a two-key, fixed ratio schedule of food-reinforced key pecking. CP-135,807 and the structurally unrelated 5-HT1D agonist CP-286,601 fully and dose-dependently substituted for the training dose. In contrast, little substitution was observed following administration of 8-OH-DPAT, a potent 5-HT1A agonist, the 5-HT1B agonist CP-94,253, or the serotonin reuptake inhibitor sertraline. In addition, the discriminative stimulus produced by CP-135,807 was not blocked by WAY 100,635, a selective 5-HT1A antagonist, but was completely and dose-dependently antagonized by the selective 5-HT1D antagonist, GR 127935. In subjects trained under a multiple schedule of punished and unpunished responding, 8-OH-DPAT produced large increases in punished responding while having little effect on unpunished responding. In contrast, CP-135,807 and CP-94,253 produced no antipunishment effects, while GR 127935 produced modest increases in punished responding. Collectively, these results suggest that CP-135,807 produces centrally mediated psychoactive effects that differ distinctly from those of 5-HT1A agonists.
Assuntos
Indóis/farmacologia , Piridinas/farmacologia , Receptores de Serotonina/fisiologia , Agonistas do Receptor de Serotonina/farmacologia , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Columbidae , Condicionamento Operante/efeitos dos fármacos , Aprendizagem por Discriminação/efeitos dos fármacos , Discriminação Psicológica/efeitos dos fármacos , Relação Dose-Resposta a Droga , Indóis/antagonistas & inibidores , Masculino , Oxidiazóis/farmacologia , Piperazinas/farmacologia , Punição , Piridinas/antagonistas & inibidores , Antagonistas da Serotonina/farmacologiaAssuntos
Indóis/síntese química , Pirrolidinas/síntese química , Agonistas do Receptor de Serotonina/síntese química , Indóis/farmacologia , Pirrolidinas/farmacologia , Receptores de Serotonina/efeitos dos fármacos , Receptores de Serotonina/metabolismo , Serotonina/metabolismo , Agonistas do Receptor de Serotonina/farmacologia , EstereoisomerismoAssuntos
Indóis/síntese química , Receptores de Serotonina/efeitos dos fármacos , Agonistas do Receptor de Serotonina/síntese química , Indóis/metabolismo , Indóis/farmacologia , Conformação Molecular , Estrutura Molecular , Agonistas do Receptor de Serotonina/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade , Sumatriptana/metabolismo , Sumatriptana/farmacologiaAssuntos
3',5'-GMP Cíclico Fosfodiesterases/antagonistas & inibidores , Inibidores de Fosfodiesterase/síntese química , Piridinas/síntese química , Administração Oral , Animais , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5 , Cães , Disfunção Erétil/tratamento farmacológico , Técnicas In Vitro , Masculino , Relaxamento Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , Pênis/efeitos dos fármacos , Pênis/fisiologia , Inibidores de Fosfodiesterase/química , Inibidores de Fosfodiesterase/farmacocinética , Inibidores de Fosfodiesterase/farmacologia , Piridinas/química , Piridinas/farmacocinética , Piridinas/farmacologia , Coelhos , Ratos , Relação Estrutura-AtividadeRESUMO
3-(1,2,5,6-Tetrahydro-4-pyridyl)-5-n-propoxyindole (CP-96,501) was found to be more selective ligand at the serotonin 5-HT1B receptor than the commonly used 5-HT1B agonist, 3-(1,2,5,6-tetrahydro-4-pyridyl)-5-methoxyindole (RU 24969). In rat brain membranes, the tritiated derivative, [3H]CP-96,501, was found to bind with a high affinity (KD, 0.21 nM) to a single binding site (nH, 1.0). The receptor density of this site (Bmax, 72 fmol/mg of protein) matched that of the 5-HT1B receptor determined with [3H]5-HT. Competition curves of 16 serotonergic compounds in [3H]CP-96,501 binding also indicated a single binding site. The rank order of their binding affinities with this new radioligand showed a high degree of correlation with their affinities at the 5-HT1B receptor determined with [3H]5-HT or [125I]iodocyanopindolol. Serotonergic compounds displayed competitive inhibition of [3H]CP-96,501 binding. In the presence of 5'-guanylylimidodiphosphate [Gpp(NH)p], [3H]CP-96,501 to displace [125I]iodocyanopindolol binding was also decreased. These findings are consistent with the agonist nature of CP-96,501. The results of this study suggest that [3H]CP-96,501 is a useful agonist radioligand for the 5-HT1B receptor.
Assuntos
Encéfalo/metabolismo , Indóis/metabolismo , Receptores de Serotonina/metabolismo , Animais , Ligação Competitiva , Nucleotídeos de Guanina/farmacologia , Indóis/antagonistas & inibidores , Indóis/química , Ligantes , Ratos , TrítioRESUMO
The 5-HT3 receptor antagonist tropisetron (ICS 205-930) was found to be a potent and selective partial agonist at alpha7 nicotinic receptors. Two other 5-HT3 receptor antagonists, ondansetron and LY-278,584, were found to lack high affinity at the alpha7 nicotinic receptor. Quinuclidine analogues (1 and 2) of tropisetron were also found to be potent and selective partial agonists at alpha7 nicotinic receptors.
Assuntos
Indóis/farmacologia , Agonistas Nicotínicos/farmacologia , Receptores Nicotínicos/efeitos dos fármacos , Antagonistas da Serotonina/farmacologia , Animais , Membrana Celular/química , Hipocampo/ultraestrutura , Concentração Inibidora 50 , Intestino Delgado/ultraestrutura , Ligantes , Potenciais da Membrana/efeitos dos fármacos , Camundongos , Oócitos/efeitos dos fármacos , Oócitos/fisiologia , Ligação Proteica , Ratos , Receptores Nicotínicos/metabolismo , Relação Estrutura-Atividade , Tropizetrona , Xenopus , Receptor Nicotínico de Acetilcolina alfa7RESUMO
We studied the dural plasma protein extravasation response after unilateral electrical stimulation of the trigeminal ganglion in mice lacking serotonin 5-HT1B (5-HT1D beta) receptors by modifying a technique previously described in rats or guinea pigs. We investigated the inhibitory effects of six 5-HT1 receptor agonists in this model: 3-(1,2,5,6-tetrahydropyrid-4-yl)pyrrolo[3,2-b]pyrid-5-one (CP-93,129), sumatriptan, serotonin-5-O-carboxymethyl-glycyl -tyrosinamide (GTI), 5-methylaminosulfonylmethyl-3-(N-methylpyrrolidin-2R -ylmethyl)-1H-indole (CP-122,288), 5-carboxamido-tryptamine (5-CT), and dihydroergotamine. The plasma extravasation response did not differ between wild-type and mutant after vehicle injection. The potency of sumatriptan, CP-122,288, CP-93,129, and 5-CT in wild-type mice was similar to that previously reported for rats. CP-122,288 (1 nmol kg), 5-CT (1 nmol/kg), and dihydroergotamine (72 nmol/kg) inhibited plasma protein extravasation within dura mater after electrical trigeminal ganglion stimulation in both wild-type and knockout mice, which suggests that these agonists act predominantly via receptors other than 5-HT1B. Unlike the wild-type mice, CP-93,129 (1.4 mumol/kg), a specific 5-HT1B receptor agonist, had no effect in knockout mice. The same held true for sumatriptan (0.7 mumol/kg) and GTI (0.6 mumol/kg). These results suggest that CP-93,129, sumatriptan, and GTI exert their effects via 5-HT1B (5-HT1D beta) receptors in mice.
Assuntos
Di-Hidroergotamina/farmacologia , Dipeptídeos/farmacologia , Piridinas/farmacologia , Pirróis/farmacologia , Pirrolidinas/farmacologia , Receptores de Serotonina/efeitos dos fármacos , Agonistas do Receptor de Serotonina/farmacologia , Serotonina/análogos & derivados , Sumatriptana/análogos & derivados , Sumatriptana/farmacologia , Gânglio Trigeminal/efeitos dos fármacos , Animais , Permeabilidade Capilar/efeitos dos fármacos , Camundongos , Camundongos Knockout , Serotonina/farmacologiaRESUMO
The design and synthesis of a novel scaffold for potent and selective PDE5 inhibitors are described. Compound 3a was more potent (PDE5 IC50=0.31 nM) and selective (>10,000-fold vs PDE1 and 160-fold selective vs PDE6) PDE5 inhibitor than sildenafil.