RESUMEN
A novel series of pyridopyrimidine analogues 9 was identified as potent adenosine kinase inhibitors based on the SAR and computational studies. Substitution of the C7 position of the pyridopyrimidino core with C2' substituted pyridino moiety increased the in vivo potency and enhanced oral bioavailability of these adenosine kinase inhibitors.
Asunto(s)
Adenosina Quinasa/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Pirimidinas/farmacología , Adenosina Quinasa/metabolismo , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Modelos Moleculares , Conformación Molecular , Morfolinas/química , Morfolinas/farmacología , Pirimidinas/síntesis química , Pirimidinas/química , Relación Estructura-ActividadRESUMEN
Adenosine (ADO) is an endogenous homeostatic inhibitory neuromodulator that reduces cellular excitability at sites of tissue injury and inflammation. Inhibition of adenosine kinase (AK), the primary metabolic enzyme for ADO, selectively increases ADO concentrations at sites of tissue trauma and enhances the analgesic and antiinflammatory actions of ADO. Optimization of the high-throughput screening lead, 4-amino-7-aryl-substituted pteridine (5) (AK IC(50) = 440 nM), led to the identification of compound 21 (4-amino-5-(3-bromophenyl)-7-(6-morpholino-pyridin-3-yl)pyrido [2,3-d]pyrimidine, ABT-702), a novel, potent (AK IC(50) = 1.7 nM) non-nucleoside AK inhibitor with oral activity in animal models of pain and inflammation.
Asunto(s)
Adenosina Quinasa/antagonistas & inhibidores , Antiinflamatorios no Esteroideos/síntesis química , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Morfolinas/síntesis química , Morfolinas/farmacología , Pirimidinas/síntesis química , Pirimidinas/farmacología , Animales , Antiinflamatorios no Esteroideos/farmacología , Diseño de Fármacos , Formaldehído , Humanos , Modelos Moleculares , Conformación Molecular , Dimensión del Dolor , Ratas , Células Tumorales CultivadasRESUMEN
The available evidence suggests that daily injections of selective dopamine (DA) D2 receptor agonists to DA depleted rats typically leads to behavioral sensitization, but the effects of repeated treatment with selective DA D1 receptor agonists are more equivocal. In this study we examined the effects of acute and repeated treatment with DA receptor agonists with various D1/D2 receptor selectivities on rotation and striatal c-fos activation in rats with unilateral DA depletions. Lesioned rats were treated daily for 10 d with either the novel, selective DA D1 receptor agonist, A-85653, the DA D2 receptor agonist, quinpirole, a combination of these compounds, or the indirect D1/D2 receptor agonist levodopa (L-DOPA). Over days, rats given A-85653 alone showed behavioral tolerance, whereas those given either quinpirole or L-DOPA demonstrated behavioral sensitization. Repeated A-85653 + quinpirole treatment s lead to an increase in response magnitude early in the testing sessions and this was accompanied by a reduction in response duration over days. Quantitative analysis of striatal c-fos activation was also conducted in lesioned rats treated acutely or repeatedly with A-85653, A-85653 + quinpirole or L-DOPA. Numbers of Fos-immunoreactive nuclei were sharply reduced after the agonist challenge in all animals given repeated, compared to acute, drug treatment, despite enhanced levels of rotation by rats given quinpirole + A-85653 or L-DOPA repeatedly. These results suggest that desensitization may develop at the DA D1 receptor as a consequence of repeated stimulation, and that the behavioral sensitization seen after repeated L-DOPA treatment may primarily involve the DA D2 receptor.
Asunto(s)
Benzopiranos/farmacología , Cuerpo Estriado/efectos de los fármacos , Agonistas de Dopamina/farmacología , Ergolinas/farmacología , Genes fos , Levodopa/farmacología , Animales , Cuerpo Estriado/metabolismo , Inmunohistoquímica , Masculino , Quinpirol , Ratas , Ratas Sprague-DawleyRESUMEN
A-77636, ((1R,3S) 3-(1'-adamantyl)-1-aminomethyl-3,4-dihydro-5,6-dihydroxy-1H-2-benz opyran hydrochloride), is a selective dopamine D1 receptor agonist. In a battery of receptor binding assays, A-77636 shows the highest affinity (pKi = 7.40 +/- 0.09; Ki = 39.8 nM) for the dopamine D1 receptor. A-77636 is an agonist at the dopamine D1 receptors in the fish retina (pEC50 = 8.13; EC50 = 1.1 nM; intrinsic activity = 102% of dopamine) and the rat caudate-putamen (pEC50 = 8.97; intrinsic activity = 134% of dopamine). The compound is functionally inactive at dopamine D2 receptors (EC50 > 10 microM). In rats with unilateral 6-OHDA (6-hydroxydopamine) lesions of the nigro-striatal dopaminergic pathway, A-77636 elicits prolonged (> 20 h) contralateral turning that is blocked by SCH 23390, a D1 receptor antagonist, but not by haloperidol at doses selective for the dopamine D2 receptor. Higher doses of A-77636 produce forelimb clonus in rats and mice. When tested in marmosets treated with MPTP to induce a parkinsonian-like state, A-77636 increases locomotor activity and decreases the severity of the parkinsonian-like symptoms: the compound is active after either subcutaneous or oral administration. A-77641, the optical antipode of A-77636, has a lower affinity towards the dopamine D1 receptor (pKi = 5.14, Ki = 7200 nM), is less potent as a dopamine D1 receptor agonist (pEC50 = 5.65; EC50 = 2200 nM), fails to elicit turning in the 6-OHDA-lesioned rat, and lacks antiparkinsonian efficacy in the MPTP-treated marmoset.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Adamantano/análogos & derivados , Antiparkinsonianos/farmacología , Benzopiranos/farmacología , Dopaminérgicos/farmacología , Enfermedad de Parkinson Secundaria/tratamiento farmacológico , Receptores de Dopamina D1/metabolismo , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/farmacología , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/farmacología , Adamantano/administración & dosificación , Adamantano/metabolismo , Adamantano/farmacología , Administración Oral , Animales , Antiparkinsonianos/administración & dosificación , Antiparkinsonianos/metabolismo , Benzazepinas/farmacología , Benzopiranos/administración & dosificación , Benzopiranos/metabolismo , Sitios de Unión , Callithrix , Línea Celular , Dopaminérgicos/administración & dosificación , Dopaminérgicos/metabolismo , Peces , Inyecciones Subcutáneas , Ratones , Actividad Motora/efectos de los fármacos , Oxidopamina/farmacología , Enfermedad de Parkinson Secundaria/inducido químicamente , Ratas , Receptores de Dopamina D1/efectos de los fármacosRESUMEN
The synthesis and dopaminergic activity of a series of C3 and nitrogen-substituted 1-(aminomethyl)-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyrans (isochromans) is described. The synthesis of the compounds was stereospecific for the 1,3 cis isomer, and the enantioselective synthesis of both enantiomers of one of the analogues (20) was achieved. It was determined that all of the dopaminergic activity resides in the [1R,3S] isomer. Generally, substitution at the C3 position provided compounds with very high potency (less than 10 nm EC50) and selectivity for the D1 receptor, with a wide range of intrinsic activities (60-160%). Analogues containing C3 substituents including aryl, arylalkyl, and cyclic and acyclic alkyl groups showed a marked enhancement of dopaminergic activity compared to the unsubstituted compound. As a class, the drugs were orally active in the rat rotation model with a very long duration of action.