Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:4.6.1.1 (adenylate cyclase)
19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The antagonistic effect of dopamine (DA) D-1 and D-2 antagonists against circling behaviour induced by various DA agonists in 6-OHDA-lesioned rats has been investigated. DA D-1/D-2 selectivity of agonists in vitro was measured by the stimulatory effect on DA-sensitive adenylate cyclase in rat striatal homogenates (D-1), the inhibitory effect on electrically-induced release of 3H-DA in rabbit striatal slices (D-2) and the affinity to 3H-piflutixol (D-1) and 3H-spiroperidol (D-2) binding sites in rat striatal membranes. The contralateral circling behaviour induced by the DA D-1 agonist SK & F 38393 was blocked by the DA D-1 antagonist, SCH 23390, and by the mixed DA D-1/D-2 antagonist cis(Z)-flupentixol, but was not influenced by the DA D-2 antagonists spiroperidol and clebopride. In contrast, circling behaviour induced by the preferential DA D-2 agonists pergolide and LY 171555 was blocked by clebopride, spiroperidol, and cis(Z)-flupentixol, but weakly or not influenced by SCH 23390. Apomorphine-induced circling behaviour was blocked by cis(Z)-flupentixol, partially antagonized by SCH 23390 and clebopride but not inhibited by spiroperidol, although the time-course of circling was changed. Combinations of SCH 23390 with spiroperidol or clebopride in low doses completely blocked the effect of apomorphine. These results indicate that DA D-1 and D-2 receptors mediate circling behaviour through separate mechanisms which can be independently manipulated with respective agonists and antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Differential involvement of dopamine D-1 and D-2 receptors in the circling behaviour induced by apomorphine, SK & F 38393, pergolide and LY 171555 in 6-hydroxydopamine-lesioned rats. 286 Jun 89

Measuring adenylate cyclase activity as a biochemical index of dopamine (DA) receptors, it was found that the selective D1 DA receptor agonist, SKF 82526, was able to stimulate the cAMP formation in rabbit renal and mesenteric arteries, an effect blocked by haloperidol and by SCH 23390. The D2 DA receptor agonist, bromocriptine, elicited a concentration-dependent inhibition of adenylate cyclase activity in both arteries of either normal or 6-hydroxydopamine pretreated rabbits, this effect being prevented by (-)-sulpiride but not by (+)-sulpiride. These data indicate that both D1 and D2 postsynaptic DA receptors, associated with stimulation or inhibition of adenylate cyclase activity, are present on the wall of rabbit renal and mesenteric arteries.
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PMID:Postsynaptic D1 and D2 dopamine receptors are present in rabbit renal and mesenteric arteries. 286 3

Unilateral degeneration of the nigro-striatal dopaminergic pathway with 6-hydroxydopamine induced contralateral rotations to apomorphine injection, increased [3H]-spiroperidol binding and enhanced sensitivity of adenylate cyclase to dopamine stimulation in lesioned striata. Prolonged L-DOPA administration counteracted the increased density of [3H]-spiroperidol binding sites but further enhanced the hypersensitivity of adenylate cyclase to dopamine. Also apomorphine-induced contralateral rotations were potentiated. This effect was antagonized by SCH-23390. These results suggest that dopaminergic D1 and D2 receptors are differently affected by prolonged L-DOPA treatment.
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PMID:Differential effect of repeated treatment with L-dopa on dopamine-D1 or -D2 receptors. 287 16

In the isolated superior cervical ganglion of the rat, activation of either DA1 or DA2 receptors leads to inhibition of ganglionic transmission. Using dopamine as well as relatively selective dopamine receptor agonists and antagonists we have performed electrophysiological as well as biochemical experiments to study the nature of dopamine receptors in this sympathetic ganglion. Fenoldopam, a selective DA1 receptor agonist caused marked inhibition of the compound postganglionic action potential evoked by stimulation of preganglionic nerve. The inhibitory effect of fenoldopam was antagonized by the DA1 receptor antagonist R-sulpiride but not by the DA2 receptor antagonist S-sulpiride. However, the more potent and selective DA1 receptor antagonist SCH-23390 failed to antagonize ganglion blocking effect of fenoldopam indicating that DA1 receptor in sympathetic ganglia is different from that in blood vessels. The superior cervical ganglion also contains DA2 receptors inasmuch as quinpirole, a DA2 receptor agonist, caused inhibition of ganglionic transmission which was antagonized by S-sulpiride but not by R-sulpiride. The existence of both subtypes of dopamine receptor in the superior cervical ganglion was ascertained further as dopamine itself caused inhibition of ganglionic transmission which was antagonized by either S- or R-sulpiride. Again, however, the DA1 receptor antagonist SCH-23390 failed to antagonize the ganglion blocking effect of dopamine. To characterize further the ganglionic DA1 receptor we sought to demonstrate whether or not ganglionic DA1 receptor is linked to the enzyme adenylate cyclase as is known to be the case for peripheral DA1 or central D1 dopamine receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Activation of DA1 receptors by dopamine or fenoldopam increases cyclic AMP levels in the renal artery but not in the superior cervical ganglion of the rat. 287 13

Inhibitory activities of a series of analogs of SCH 23390 ((R)-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3- benzazepine) in which the 7-chloro group was substituted by bromo, fluoro, methyl and methoxy groups, respectively, were compared in three tests for D1 and DA1 dopamine (DA) receptor antagonism: inhibition of DA-induced renal vasodilation in the anesthetized dog (DA1 receptor model), inhibition of DA-stimulated adenylate cyclase in the striatum of adult female rats (D1 receptor model) and displacement of [3H]SCH 23390 in the striatal homogenates of male rats. In addition the D2 receptor affinity of each of the compounds chosen was assessed via displacement of [3H]spiperone binding from rat striatum. S-enantiomers of the Cl and CH3 analogs were 200- to 700-fold weaker than the respective R-enantiomers in all three tests. The activity of all the R-enantiomers was in the nanomolar range and varied no more than 8-fold in all three tests. The F analog in the ligand binding test was the only exception, which was 30-fold weaker than the C1 analog. All of the R-enantiomers studied showed much weaker affinity for the D2 receptor, as assessed by displacement of [3H]spiperone binding. Similar enantiomer selectivity and parallel affinities of the R-enantiomers in the prototype models for D1 and DA1 receptors strengthen the evidence in support of identity between the D1 and DA1 dopamine receptors. These results further indicate that displacement of SCH 23390 in the ligand binding test reflects affinity of a compound for D1 and DA1 dopamine receptors.
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PMID:Relative activities of SCH 23390 and its analogs in three tests for D1/DA1 dopamine receptor antagonism. 287 16

By using selective dopamine (DA) receptor agonists and antagonists, we have demonstrated previously the presence of DA-2- and DA-1-like DA receptors in the stellate ganglia of the dog. Activation of either DA-2- or DA-1-like receptors by quinpirole or fenoldopam, respectively, leads to inhibition of ganglionic transmission. In the present study we have examined the involvement of DA receptor subtypes in the action of DA on ganglionic transmission. Inasmuch as stimulation of DA receptors is linked to the activation (DA-1) or inhibition (DA-2) of the enzyme adenylate cyclase, we have also measured the accumulation of cyclic AMP (cAMP) for biochemical characterization of ganglionic DA receptors. In isolated stellate ganglia treated with phentolamine and propranolol, DA caused concentration-dependent inhibition of ganglionic transmission as evidenced by reductions in the amplitude of the evoked postganglionic compound action potentials. The inhibitory effect of DA on ganglionic transmission was antagonized by both the DA-1 receptor antagonist, R-sulpiride, and the DA-2 receptor antagonist, S-sulpiride. However, the more potent and selective DA-1 receptor antagonist, SCH-23390, failed to antagonize the DA-induced inhibition of ganglionic transmission. Isolated stellate ganglia were also utilized for the measurement of cAMP. Neither DA nor the selective DA-1 receptor agonist, fenoldopam, caused any significant changes in cAMP, suggesting the lack of an adenylate cyclase-linked DA-1 receptor in the ganglia. On the other hand, beta adrenoceptor activation by isoproterenol produced a 3-fold increase in cAMP content of the stellate ganglia.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of dopamine receptor activation on ganglionic transmission and cyclic AMP levels in the stellate ganglia and renal arteries of the dog. 287 5

The binding of 3H-SCH 23390 to membranes from rat and mouse brain tissue has been investigated. The binding was saturable and reached equilibrium after 60 minutes. Nonspecific binding was low. Association and dissociation rates were Mg++-sensitive. In almost all respects the binding of 3H-SCH 23390 was comparable to the binding of 3H-piflutixol and 3H-cis(Z)-flupentixol. The density of binding sites in striatum was greater than in limbic structures which in turn was greater than in frontal cortex. The density of binding sites in these structures were comparable with those of 3H-piflutixol and 3H-cis(Z)-flupenthixol, 2-3 times higher than the D-2-receptor density. Whereas an increase was seen in 3H-SCH 23390 binding. The binding was decreased approximately 72% 3 weeks after unilateral kainic acid lesion whereas that of 3H-spiperone was only decreased 56%. Finally, the affinities of neuroleptics to the 3H-SCH 23390-binding sites correlated to the affinities to 3H-piflutixol-binding sites and to the effects on DA-sensitive adenylate cyclase. Agonist competition curves were shallow and the data best fit a two-site model composed of a high and a low affinity component. Thus, 3H-SCH 23390 is regarded as a highly selective ligand for brain dopamine D-1 receptors in vitro.
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PMID:Characterization of binding of 3H-SCH 23390 to dopamine D-1 receptors. Correlation to other D-1 and D-2 measures and effect of selective lesions. 288 76

We studied the possible functional modifications of both D-1 and D-2 dopamine (DA) receptor subtypes following repeated administration of DA antagonists that act selectively on a single class of DA receptors. The functional state of D-1 and D-2 DA receptors in particular was evaluated by measuring SKF 82526-stimulated and bromocriptine-inhibited adenylate cyclase activity in different brain regions of rats treated with saline, SCH 23390, or (-)sulpiride for 21 days. The results indicate that chronic blockade of D-1 DA receptors in striatum, nucleus accumbens, and substantia nigra by SCH 23390 induced up-regulation of the D-1 receptors without changing the functional activity of D-2 receptors. Likewise, chronic blockade of D-2 DA receptors by (-)sulpiride caused up-regulation of D-2 but not D-1 DA receptors in striatum, nucleus accumbens, substantia nigra and pituitary. SCH 23390 or (-)sulpiride did not modify the functional activity of either D-1 or D-2 DA receptors located in frontal cortex and hippocampus. In conclusion, these results indicate that chronic treatment with selective D-1 or D-2 DA receptor blockers induces a receptor-specific up-regulation which involves the DA receptors located in the nigrostriatal system and pituitary but not those in the limbic-cortical areas.
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PMID:Repeated administration of (-)sulpiride and SCH 23390 differentially up-regulate D-1 and D-2 dopamine receptor function in rat mesostriatal areas but not in cortical-limbic brain regions. 288 36

CK 204-933 displaces [3H]dopamine and [3H]spiperone with high affinity from D-1 and D-2 recognition sites in membranes of calf caudate. Results from functional in vitro tests suggest that it is a partial agonist at D-1 receptors and an antagonist at D-2 receptors. These opposite effects at dopamine receptor subtypes are also expressed in vivo. For instance, in 6-hydroxydopamine lesioned rats, CK 204-933 induces contralateral rotations which are antagonised by SCH 23390 but not by sulpiride. On the other hand, CK 204-933 induces a long lasting increase of dopamine turnover in rat striatum and antagonises apomorphine-induced gnawing behaviour in rats. CK 204-933 increases prolactin serum levels in rats after subcutaneous administration, whereas after oral administration a moderate decrease of prolactin serum levels was seen. The latter effect is probably due to the formation of active metabolites. CK 204-933 exhibits also a high affinity to [3H]prazosin binding sites and antagonises serotonin-mediated stimulation of adenylate cyclase in rat hippocampus. On the other hand, CK 204-933 has no effect of only very weak effects on noradrenaline and serotonin release from rat cerebral cortex slices, which is consistent with its weak effects on noradrenaline- and serotonin-turnover in rat brain. Based on these properties it is suggested that CK 204-933 could be of therapeutic value in brain diseases associated with disturbances of monoaminergic neurotransmission.
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PMID:Biochemical, behavioural, and endocrine effects of CK 204-933, a novel 8 beta-ergolene. 288 30

Dopamine increases cyclic AMP production in crude membrane preparations of cockroach brain with plateaus in cyclic AMP production occurring between 1-10 microM and at 10 mM. Maximal production of cyclic AMP is 2.25 fold greater than that of control values. Octopamine also increases cyclic AMP production with a Ka of 1.4 microM and maximal production 3.5 fold greater than that of control. 5-Hydroxytryptamine does not increase cyclic AMP production. The effects of octopamine and dopamine are fully additive. The vertebrate dopamine agonists ADTN and epinine stimulate the dopamine-sensitive adenylate cyclase (AC) with Ka values of 4.5 and 0.6 microM respectively and with maximal effectiveness 1.7 fold greater than that of control. The selective D2-dopamine agonist LY-171555 stimulates cyclic AMP production to a similar extent with a Ka of 50 microM. Other dopamine agonists (apomorphine, SKF-82526, SKF-38393) have no stimulatory effects. The octopamine-sensitive AC is inhibited by a variety of antagonists known to affect octopamine and dopamine receptors, with the following order of potency: mianserin greater than phentolamine greater than cyproheptadine greater than piflutixol greater than cis-flupentixol greater than SCH-23390 greater than (+)-butaclamol greater than SKF-83566 greater than SCH-23388 greater than sulpiride greater than spiperone greater than haloperidol. The dopamine-sensitive AC is inhibited by the same compounds with the following order of potency: piflutixol greater than cis-flupentixol greater than (+)-butaclamol greater than spiperone greater than or equal to SCH-23390 greater than cyproheptadine greater than SKF-83566 greater than SCH 23388 greater than mianserin greater than phentolamine greater than sulpiride greater than haloperidol. With the exception of mianserin, 3H-piflutixol is displaced from brain membranes by dopamine antagonists with an order of potency similar to that observed for the inhibition of dopamine-sensitive AC. The results indicate that the octopamine- and dopamine-sensitive AC in cockroach brain can be distinguished pharmacologically and the dopamine receptors coupled to AC have pharmacological characteristics distinct from vertebrate D1- and D2-dopamine receptors.
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PMID:Pharmacological characterisation of the dopamine-sensitive adenylate cyclase in cockroach brain: evidence for a distinct dopamine receptor. 289 4


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