RESUMEN
In rat neocortical slices maintained in Mg2+-free Krebs medium, baclofen depressed the rate of spontaneous discharges in a concentration-dependent manner (EC50 = 4.5 microM). This depression was reversibly antagonised by 5-(S,R)-hydroxymethyl-5-methylmorpholinyl-2-(R,S)-acetic acid (Sch 54679) and 2-(R,S)-5-[spirocyclopentyl]-morpholinyl-acetic acid (Sch 51324) (respective pA2 values of 5.8+/-0.15 and 5.4+/-0.2). In electrically-stimulated slices preloaded with [3H]gamma-aminobutyric acid (GABA), Sch 54679 (EC50 = 3 microM) was 2.3 times more potent than Sch 51324 (EC50 = 7 microM) in increasing [3H]GABA release through antagonism of GABA(B) autoreceptors. These structurally novel analogues may be pharmacologically useful for elucidating GABA(B) receptor functions.
Asunto(s)
Antagonistas del GABA/farmacología , Antagonistas de Receptores de GABA-B , Morfolinas/farmacología , Animales , Baclofeno/farmacología , Relación Dosis-Respuesta a Droga , Estimulación Eléctrica , Electrofisiología , Agonistas del GABA/farmacología , Agonistas de Receptores GABA-B , Técnicas In Vitro , Masculino , Morfolinas/química , Neocórtex/efectos de los fármacos , Neocórtex/fisiología , Inhibidores de la Captación de Neurotransmisores/farmacología , Ácidos Nipecóticos/farmacología , Oximas/farmacología , Ratas , Ratas Sprague-Dawley , Tritio , Ácido gamma-Aminobutírico/efectos de los fármacos , Ácido gamma-Aminobutírico/metabolismoRESUMEN
The pharmacological properties of (+)-(S)-5,5-dimethylmorpholinyl-2-acetic acid (Sch 50911) were evaluated on GABA(B) receptors in rat neocortical slices. The GABA(B) receptor agonist, baclofen, produced a concentration-dependent depression of the frequency of spontaneous discharges in slices maintained in Mg2+-free Krebs medium with an EC50 of 6 microM, reversibly antagonised by Sch 50911 (5, 10 and 25 microM) with an apparent pA2 of 6.0 +/- 0.1. The (-) enantiomer Sch 50910 (500 microM) and the racemic des-methyl analogue Sch 48588 (500 microM) were inactive. In slices preloaded with [3H]GABA, Sch 50911 antagonised GABA(B) autoreceptors, increasing the electrically-stimulated 3H overflow in a concentration-dependent manner, with an IC50 of 3 microM. The maximal effect (148 +/- 10.5%) was found at 10 microM, but at 50 microM the response was reduced to 67 +/- 19%. In contrast, evoked release was unaffected by Sch 50910 (100 microM) whilst Sch 48588 at 100 microM increased the overflow by 51.3 +/- 11.6%. In summary, Sch 50911 is a relatively potent antagonist of considerable potential in studies of GABA(B) receptor function.
Asunto(s)
Antagonistas del GABA/farmacología , Antagonistas de Receptores de GABA-B , Morfolinas/farmacología , Neocórtex/efectos de los fármacos , Animales , Baclofeno/farmacología , Relación Dosis-Respuesta a Droga , Técnicas In Vitro , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
A series of gamma-aminobutyric acid (GABA) 1 analogs was prepared in which the carboxylic acid group of GABA was replaced with a sulfinic acid group and their affinity for the GABAB receptor investigated.
Asunto(s)
Receptores de GABA-B/metabolismo , Ácidos Sulfínicos/síntesis química , Ácido gamma-Aminobutírico/síntesis química , Relación Estructura-Actividad , Ácidos Sulfínicos/metabolismo , Ácido gamma-Aminobutírico/metabolismoRESUMEN
Experiments were conducted to characterize the pharmacology of SCH 50911 ((+)-5,5-dimethyl-2-morpholineacetic acid hydrochloride), a structurally novel GABA-B receptor antagonist. Although more potent GABA-B antagonists have been reported, in this study SCH 50911 was compared with CGP 35348, a moderately potent and selective GABA-B antagonist with acceptable in vivo activity. SCH 50911 was more potent to inhibit the binding of GABA to the GABA-B receptor in rat brain (IC50 = 1.1 microM) than CGP 35348 (IC50 = 62 microM). SCH 50911 had no binding affinity for GABA-A, histamine H1, histamine H3, dopamine D1, dopamine D2, serotonin 5-HT2, or muscarinic m1, m2, or m4 receptors. However, SCH 50911 (IC50 = 2.2 microM) was active in a nonspecific muscarinic receptor binding assay, but was devoid of muscarinic agonist or antagonist activity in the isolated guinea pig ileum. SCH 50911 blocked inhibitory responses to baclofen of the guinea pig trachea in a competitive manner (pA2 = 5.8 +/- 0.004). CGP 35348 was 19-fold less potent in this assay (pA2 = 4.6 +/- 0.15). In vivo, SCH 50911 (ED50 = 2.9 mg kg-1, s.c.) and CGP 35348 (ED50 = 5.8 mg kg-1, s.c.) blocked the antitussive effects of baclofen in the guinea pig. In the cat, both SCH 50911 (10 mg kg-1, i.v.) and CGP 35348 (10 mg kg-1, i.v.) shifted the antitussive dose response relationship for baclofen to the right.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Antagonistas del GABA/farmacología , Antagonistas de Receptores de GABA-B , Morfolinas/farmacología , Administración Oral , Animales , Antitusígenos/antagonistas & inhibidores , Antitusígenos/farmacología , Baclofeno/antagonistas & inhibidores , Baclofeno/farmacología , Células CHO , Gatos , Colinérgicos/farmacología , Cricetinae , Antagonistas del GABA/administración & dosificación , Antagonistas del GABA/metabolismo , Cobayas , Humanos , Íleon/efectos de los fármacos , Íleon/fisiología , Técnicas In Vitro , Masculino , Morfolinas/administración & dosificación , Morfolinas/metabolismo , Contracción Muscular/efectos de los fármacos , Unión Proteica , Ratas , Ratas Sprague-Dawley , Receptores de GABA-B/metabolismo , Tráquea/efectos de los fármacos , Tráquea/fisiologíaRESUMEN
A novel class of antiinflammatory drugs, which are substituted derivatives of the fused tricyclic system 6-hydroxypyrimido[2,1-f]purine-2,4,8(1H,3H,9H)-trione, is described. Synthetic procedures and structure determination with the assistance of X-ray crystallography are discussed. Semiempirical molecular orbital calculations are used to investigate the relative stability of the possible isomers and tautomers of the title compounds. A biological profile of the class, and of several of the more potent analogues, in several antiinflammatory models, including the adjuvant-induced arthritis and the collagen II models, is defined. Several members of the class are shown to possess extremely low ulcerogenic effects in spite of exhibiting cyclooxygenase inhibition. A preliminary bioavailability study of two of the lead structures is presented. The compounds 6-72 appear to constitute a class of drugs that shows interesting potential antiarthritic activity and also exhibits an activity profile different from that of the standard classical NSAI drugs, as determined by a comparison of the profile of this class of drug with that of several standard agents. Certain findings from toxicological studies have precluded the further development of compounds within this group, although related structural types are being investigated.