RESUMEN
The in vivo properties of a series of 2-arylindole NK(1) antagonists have been improved, by modification of the amide substituent. The 1-(2-methoxyphenyl)piperazine amide was identified as a major area of metabolism in the lead compound 1. Replacement of this amine moiety by a 4-benzyl-4-hydroxypiperidine resulted in a compound 18 with reduced clearance and improved central duration of action.
Asunto(s)
Amidas/química , Indoles/farmacocinética , Neuroquinina A/antagonistas & inhibidores , Administración Oral , Animales , Disponibilidad Biológica , Cricetinae , Evaluación Preclínica de Medicamentos , Concentración 50 Inhibidora , Tasa de Depuración Metabólica , Piperazinas/química , Ratas , Relación Estructura-ActividadRESUMEN
Novel 2-aryl indole hNK1 receptor ligands were prepared utilising palladium cross-coupling chemistry of a late intermediate as a key step. Compounds with high hNK1 receptor binding affinity and good brain penetration (e.g., 9d) were synthesised.
Asunto(s)
Indoles/síntesis química , Indoles/farmacología , Antagonistas del Receptor de Neuroquinina-1 , Animales , Conducta Animal/efectos de los fármacos , Unión Competitiva/efectos de los fármacos , Células CHO , Cricetinae , Electrones , Gerbillinae , Indoles/farmacocinética , Conformación Molecular , Nitrógeno/química , Proteínas Recombinantes/efectos de los fármacos , Relación Estructura-Actividad , Sustancia P/metabolismoRESUMEN
7-azaindole compounds bearing a cyclic amine moiety linked by a one or two carbon chain attached at the 2- or 3-position were synthesised and evaluated as potential dopamine D4 ligands. Highest affinity and selectivity for the D4 receptor resided in the 3-aminomethyl-7-azaindole series.
Asunto(s)
Compuestos Aza/química , Indoles/síntesis química , Receptores de Dopamina D2/metabolismo , Humanos , Indoles/química , Indoles/metabolismo , Ligandos , Estructura Molecular , Unión Proteica , Receptores de Dopamina D4 , Relación Estructura-ActividadRESUMEN
L-745,870,(3-([4-(4-chlorophenyl)piperazin-1-yl]methyl)-1H- pyrollo[2,3-b] pyridine, was identified as a selective dopamine D4 receptor antagonist with excellent oral bioavailability and brain penetration. L-745,870 displaced specific binding of 0.2 nM [3H] spiperone to cloned human dopamine D4 receptors with a binding affinity (Ki) of 0. 43 nM which was 5- and 20-fold higher than that of the standard antipsychotics haloperidol and clozapine, respectively. L-745,870 exhibited high selectivity for the dopamine D4 receptor (>2000 fold) compared to other dopamine receptor subtypes and had moderate affinity for 5HT2, sigma and alpha adrenergic receptors(IC50 < 300 nM). In vitro, L-745,870 (0.1-1 microM) exhibited D4 receptor antagonist activity, reversing dopamine (1 microM) mediated 1) inhibition of adenylate cyclase in hD4HEK and hD4CHO cells; 2) stimulation of [35S] GTPgammaS binding and 3) stimulation of extracellular acidification rate, but did not exhibit any significant intrinsic activity in these assays. Although standard antipsychotics increase dopamine metabolism or plasma prolactin levels in rodents, L-745,870 (
Asunto(s)
Antagonistas de Dopamina/farmacología , Antagonistas de los Receptores de Dopamina D2 , Piridinas/farmacología , Pirroles/farmacología , Animales , Células CHO , Cricetinae , AMP Cíclico/biosíntesis , Dopamina/metabolismo , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Humanos , Masculino , Ratones , Fenazocina/análogos & derivados , Fenazocina/metabolismo , Prolactina/metabolismo , Piridinas/metabolismo , Pirroles/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores de Dopamina D4 , SaimiriRESUMEN
This study examined the high-affinity, selective dopamine D4 receptor antagonist, L-745,870 (3-([4-(4-chlorophenyl)piperazin-1-yl]methyl)-1H-pyrrolo[2, 3-b]pyridine) in rodent behavioral models used to predict antipsychotic potential and side-effect liabilities in humans. In contrast to the classical neuroleptic, haloperidol, and the atypical neuroleptic, clozapine, L-745,870 failed to antagonize amphetamine-induced hyperactivity in mice or impair conditioned avoidance responding in the rat at doses selectively blocking D4 receptors. Furthermore, L-745,870 failed to reverse the deficit in prepulse inhibition of acoustic startle responding induced by the nonselective dopamine D2/3/4 receptor agonist apomorphine, an effect which was abolished in rats pretreated with the D2/3 receptor antagonist, raclopride (0.2 mg/kg s.c.). L-745,870 had no effect on apomorphine-induced stereotypy in the rat but did induce catalepsy in the mouse, albeit at a high dose of 100 mg/kg, which is likely to occupy dopamine D2 receptors in vivo. High doses also impaired motor performance; in rats L-745,870 significantly reduced spontaneous locomotor activity (minimum effective dose = 30 mg/kg) and in mice, L-745,870 reduced the time spent on a rotarod revolving at 15 rpm (minimum effective dose = 100 mg/kg). Altogether these results suggest that dopamine D4 receptor antagonism is not responsible for the ability of clozapine to attenuate amphetamine-induced hyperactivity and conditioned avoidance responding in rodents. Furthermore, the lack of effect of L-745,870 in these behavioral tests is consistent with the inability of the compound to alleviate psychotic symptoms in humans.