RESUMEN
Wild-type and variant forms of transthyretin (TTR), a normal plasma protein, are amyloidogenic and can be deposited in the tissues as amyloid fibrils causing acquired and hereditary systemic TTR amyloidosis, a debilitating and usually fatal disease. Reduction in the abundance of amyloid fibril precursor proteins arrests amyloid deposition and halts disease progression in all forms of amyloidosis including TTR type. Our previous demonstration that circulating serum amyloid P component (SAP) is efficiently depleted by administration of a specific small molecule ligand compound, that non-covalently crosslinks pairs of SAP molecules, suggested that TTR may be also amenable to this approach. We first confirmed that chemically crosslinked human TTR is rapidly cleared from the circulation in mice. In order to crosslink pairs of TTR molecules, promote their accelerated clearance and thus therapeutically deplete plasma TTR, we prepared a range of bivalent specific ligands for the thyroxine binding sites of TTR. Non-covalently bound human TTR-ligand complexes were formed that were stable in vitro and in vivo, but they were not cleared from the plasma of mice in vivo more rapidly than native uncomplexed TTR. Therapeutic depletion of circulating TTR will require additional mechanisms.
Asunto(s)
Reactivos de Enlaces Cruzados/química , Ligandos , Prealbúmina/metabolismo , Animales , Sitios de Unión , Humanos , Ratones , Ratones Endogámicos C57BL , Modelos Moleculares , Piperidinas/química , Prealbúmina/química , Estructura Cuaternaria de Proteína , Tiroxina/química , Tiroxina/metabolismoRESUMEN
At their clinical doses, current antipsychotic agents share the property of both dopamine D(2) and D(3) receptor blockade. However, a major disadvantage of many current medications are the observed extrapyramidal side-effects (EPS), postulated to arise from D(2) receptor antagonism. Consequently, a selective dopamine D(3) receptor antagonist could offer an attractive antipsychotic therapy, devoid of the unwanted EPS. Using SAR information gained in two previously reported series of potent and selective D(3) receptor antagonists, as exemplified by the 2,3,4,5-tetrahydro-1H-3-benzazepine 10 and the 2,3-dihydro-1H-isoindoline 11, a range of 7-sulfonyloxy- and 7-sulfonylbenzazepines has been prepared. Compounds of this type combined a high level of D(3) affinity and selectivity vs D(2) with an excellent pharmacokinetic profile in the rat. Subsequent optimization of this series to improve selectivity over a range of receptors and reduce cytochrome P450 inhibitory potential gave trans-3-(2-(4-((3-(3-(5-methyl-1,2,4-oxidiazolyl))phenyl)carboxamido)cyclohexyl)ethyl)-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine (58, SB-414796). This compound is a potent and selective dopamine D(3) receptor antagonist with high oral bioavailability and is CNS penetrant in the rat. Subsequent evaluation in the rat has shown that 58 preferentially reduces firing of dopaminergic cells in the ventral tegmental area (A10) compared to the substantia nigra (A9), an observation consistent with a prediction for atypical antipsychotic efficacy. In a separate study, 58 has been shown to block expression of the conditioned place preference (CPP) response to cocaine in male rats, suggesting that it may also have a role in the treatment of cue-induced relapse in drug-free cocaine addicts.
Asunto(s)
Antipsicóticos/síntesis química , Benzazepinas/síntesis química , Antagonistas de Dopamina/síntesis química , Antagonistas de los Receptores de Dopamina D2 , Sulfonas/síntesis química , Potenciales de Acción/efectos de los fármacos , Administración Oral , Animales , Antipsicóticos/farmacocinética , Antipsicóticos/farmacología , Benzazepinas/farmacocinética , Benzazepinas/farmacología , Disponibilidad Biológica , Células CHO , Catalepsia/inducido químicamente , Cocaína/farmacología , Condicionamiento Clásico/efectos de los fármacos , Cricetinae , Dopamina/metabolismo , Antagonistas de Dopamina/farmacocinética , Antagonistas de Dopamina/farmacología , Diseño de Fármacos , Humanos , Masculino , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/fisiología , Prolactina/sangre , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Receptores de Dopamina D3 , Relación Estructura-Actividad , Sustancia Negra/citología , Sustancia Negra/efectos de los fármacos , Sustancia Negra/fisiología , Sulfonas/farmacocinética , Sulfonas/farmacología , Área Tegmental Ventral/citología , Área Tegmental Ventral/efectos de los fármacos , Área Tegmental Ventral/fisiologíaRESUMEN
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.
Asunto(s)
Receptores de Serotonina/metabolismo , Serotoninérgicos/metabolismo , Administración Oral , Disponibilidad Biológica , Ligandos , Serotoninérgicos/farmacocinéticaRESUMEN
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.
Asunto(s)
Benzoxazinas/síntesis química , Benzoxazinas/farmacología , Receptor de Serotonina 5-HT1A/efectos de los fármacos , Inhibidores Selectivos de la Recaptación de Serotonina/síntesis química , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Antagonistas de la Serotonina/síntesis química , Antagonistas de la Serotonina/farmacología , Animales , Unión Competitiva/efectos de los fármacos , Células CHO , Callithrix , Línea Celular , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Cricetinae , Cricetulus , Cobayas , Humanos , Indicadores y Reactivos , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Modelos Moleculares , Piperazinas/farmacología , Piridinas/farmacología , Ensayo de Unión Radioligante , Ratas , Receptor de Serotonina 5-HT1B/efectos de los fármacos , Receptor de Serotonina 5-HT1D/efectos de los fármacos , Sinaptosomas/efectos de los fármacosRESUMEN
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.