RESUMEN
The in vivo preclinical pharmacodynamic profile of TD-1211, a selective opioid receptor antagonist currently under development for the treatment of opioid-induced constipation, was compared to that of the clinically studied opioid antagonists, naltrexone, alvimopan, and ADL 08-0011 (the primary active metabolite of alvimopan). The oral activity of TD-1211 was evaluated in models of gastrointestinal (GI) and central nervous system (CNS) function in the rat and dog. Oral administration of TD-1211, naltrexone, and ADL 08-0011 reversed loperamide-induced inhibition of gastric emptying and castor oil-induced diarrhea in rats and nonproductive GI circular smooth muscle contractility in dogs. Alvimopan was only efficacious in the castor oil model. Oral administration of naltrexone and ADL 08-0011, but not TD-1211 or alvimopan, was associated with a CNS withdrawal response in morphine-dependent mice, inhibition of morphine-induced anti-nociception in rat and dog hot plate tests, and hypothermia and sedation in dogs. It is concluded that TD-1211 has potent in vivo GI activity, consistent with opioid receptor antagonism, but has no significant CNS activity. The data from these studies support the clinical development of TD-1211 as a novel treatment for opioid-induced GI dysfunction.
Asunto(s)
Benzamidas/farmacología , Sistema Nervioso Central/efectos de los fármacos , Tracto Gastrointestinal/efectos de los fármacos , Antagonistas de Narcóticos/farmacología , Tropanos/farmacología , Administración Oral , Analgésicos Opioides/antagonistas & inhibidores , Analgésicos Opioides/farmacología , Animales , Benzamidas/administración & dosificación , Sistema Nervioso Central/metabolismo , Perros , Femenino , Tracto Gastrointestinal/metabolismo , Masculino , Ratones , Morfina/antagonistas & inhibidores , Morfina/farmacología , Naltrexona/administración & dosificación , Naltrexona/farmacología , Antagonistas de Narcóticos/administración & dosificación , Dolor/tratamiento farmacológico , Piperidinas/administración & dosificación , Piperidinas/farmacología , Ratas , Ratas Sprague-Dawley , Síndrome de Abstinencia a Sustancias/etiología , Tropanos/administración & dosificaciónRESUMEN
Muscarinic receptor antagonists form the mainstay of the therapeutic options for airway, bladder, and gastrointestinal smooth muscle disorders. Both M(2) and M(3) muscarinic receptors are involved in mediating smooth muscle contractility, although the relative functional contribution of each subtype, especially in the disease state, is unclear. Because the potency and selectivity of compounds for a given receptor in an in vivo setting can be dissimilar to that observed in an in vitro system, we developed an in vivo assay to simultaneously determine the absolute potency and selectivity of muscarinic receptor antagonists at M(2) and M(3) receptors using the pithed rat. Methacholine (MCh)-induced bradycardia and depressor responses were used as surrogate functional endpoints for M(2) and M(3) receptor activation, respectively. The influence of the muscarinic antagonists, tolterodine, oxybutynin, darifenacin, Ro 320-6206, solifenacin, or tiotropium on the MCh-induced responses were studied. The estimated DR(10) values (dose producing a tenfold shift in the MCh curve) of tolterodine, oxybutynin, darifenacin, Ro 320-6206, solifenacin, and tiotropium for the M(2) muscarinic receptor-mediated bradycardia were 0.22, 1.18, approximately 2.6, 0.025, 0.40, and 0.0026 mg/kg, respectively, and 0.14, 0.18, 0.11, 3.0, 0.18, and 0.0017 mg/kg, respectively, for the M(3) muscarinic receptor-mediated depressor response. In a separate set of experiments, a single intravenous dose of tiotropium was administered before a MCh curve at 1, 3, 6, or 9 h to determine if tiotropium exhibited time-dependent selectivity for the M(3) receptor as has been reported from in vitro studies. The results indicate a slight preference of tiotropium for the M(3) receptor at later time points. The pithed rat assay may serve useful for elucidating the functional contribution of M(2) and M(3) receptors to the in vivo pharmacological effects of antagonists in disease animal models.