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

---

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

Of eleven aporphine analogues tested on striatal adenylate cyclase only (-)-apomorphine and (+/-)-N-n-propyl-norapomorphine (+/-(NPA)) were effective in stimulating the cyclase from rat brain. Inactive compounds included (+/-)-isoapomorphine, (-)-1,2-dihydroxyaporphine and (+/-)-10-hydroxy-N-n-propylnoraporphine. (+)-Bulbocapnine was an effective antagonist of the stimulating effects of dopamine or (-)-apomorphine on striatal adenylate cyclase. Injection of (-)-apomorphine into the lateral ventricle of rats with unilateral 6-hydroxydopamine-induced lesions of the nigro-striatal pathway caused the animals to rotate away from the side of the lesion. Intraventricular injection of 25 mug (+/-)-10-hydroxy-N-n-propylnorapomorphine was ineffective in producing rotation. The results are discussed in relation to the structural requirements for CNS dopamine receptor agonists.
...
PMID:Aporphines. 15. Action of aporphine alkaloids on dopaminergic mechanisms in rat brain. 94 90

The involvement of dopamine receptor subtypes in the discriminative stimulus effects of cocaine was evaluated by the ability of a series of compounds selective for D1 or D2 dopamine receptors to produce discriminative stimulus effects comparable to cocaine. Male, Sprague-Dawley rats were trained to discriminate 10 mg/kg of cocaine HCI from saline in a two-lever discrimination procedure. Inhibitors of catecholamine and serotonin reuptake (GBR 12909, WIN 35,428 and mazindol), d-amphetamine, and the nonselective dopamine agonist, apomorphine, produced dose-dependent increases in cocaine-appropriate responding and fully substituted for cocaine. Cocaine methiodide, a charged, quaternary cocaine analog, did not substitute for cocaine. Neither pentobarbital, haloperidol nor SCH 23390 produced cocaine-like behavioral activity. Both D1- and D2-selective agonists with diverse structures partially substituted for cocaine, producing from 40 to 80% cocaine-appropriate responses. The D1 agonists studied were SKF 38393 and stereoisomers, SKF 75670 and CY 208-243. Dihydrexidine, a full D1 agonist for induction of adenylate cyclase activity, also only partially substituted for cocaine. The peripherally acting D1 agonist, fenoldopam, produced predominantly saline-appropriate responding that was unrelated to dose. The D2 agonists tested were pergolide, quinpirole, (-)-NPA, RU 24213, N-0434 and N-0437. The D2 antagonist haloperidol did not block the discriminative stimulus effects of cocaine. In contrast, the D1 antagonist SCH 23390 reduced the discriminative stimulus effects of cocaine by a maximum of 50%. These results suggest that both D1 and D2 receptors may play a role in the discriminative stimulus effects of cocaine but that stimulation of either dopamine receptor subtype alone is not sufficient.
...
PMID:Behavioral effects of selective dopaminergic compounds in rats discriminating cocaine injections. 167 33

Measuring adenylate cyclase activity (AC) as a biochemical index of dopamine (DA) receptor function, we obtained evidence for the presence in rabbit vasculature of both D1 receptors associated with stimulation of AC and of D2 receptors coupled with AC in an inhibitory way. The cAMP generating system in rabbit mesenteric artery was stimulated by DA and several DA agonists, an effect antagonized by the D1-receptor blocker SCH 23390 and by other neuroleptic drugs. When activation of D1 sites was impeded by SCH 23390, DA, (-)apomorphine, and (-)NPA inhibited cAMP formation. In addition, selective D2 agonists inhibited basal AC activity even when there was no D1-receptor blockade. The relative order of potency of various neuroleptics in antagonizing bromocriptine-induced inhibition of AC confirmed the D2 nature of these binding sites. Inhibition of AC activity elicited by bromocriptine remained unchanged after chemical sympathectomy, suggesting that vascular D2 receptors inhibiting AC activity are located postsynaptically in the arterial wall.
...
PMID:Identification and characterization of postsynaptic D1- and D2-dopamine receptors in the cardiovascular system. 245 58

The actions on central dopamine (DA) mechanisms of raclopride, a new substituted benzamide, were studied by means of behavioural and biochemical methods in the rat. Raclopride blocked the in vitro binding of the dopamine D2 antagonist 3H-spiperone (IC50 = 32 nM), but not of the unselective D1 antagonist 3H-flupenthixol (IC50 greater than 100,000 nM) in rat striatum, and failed to inhibit striatal DA-sensitive adenylate cyclase in vitro (IC50 greater than 100,000 nM). Raclopride caused a dose-dependent increase in the DA metabolites HVA and DOPAC in the striatum and olfactory tubercle. Behavioural studies showed that raclopride discriminates between the motor behaviours induced by the DA agonist apomorphine. Thus, unlike haloperidol, raclopride blocked apomorphine-induced hyperactivity at considerably lower doses than those inhibiting oral stereotypies. Moreover, raclopride showed a high separation between the doses for blockade of apomorphine-induced hyperactivity and those inducing catalepsy in rats. Raclopride caused a dose-dependent blockade of the specific binding of 3H-spiperone and 3H-N-n-propylnorapomorphine (3H-NPA) in vivo at doses similar to those blocking the behavioural effects of apomorphine. The maximal blockade of 3H-spiperone binding in vivo was lower for raclopride than for haloperidol. Raclopride caused a greater inhibition of 3H-NPA than of 3H-spiperone in vivo binding in the striatum. It is suggested that the ability of raclopride to discriminate between different DA-mediated functions may be attributed to a preferential blockade of a subclass of functionally coupled dopamine D2 receptors in striatal as well as in extrastriatal brain regions in the rat.
...
PMID:The selective dopamine D2 receptor antagonist raclopride discriminates between dopamine-mediated motor functions. 294 55

Rats received haloperidol, sulpiride, or clozapine in their daily drinking water for up to 1 year in clinically equivalent doses. After 12 months' drug intake, and while drug administration continued, striatal dopamine function was assessed. Haloperidol induced D-2 receptor hypersensitivity as shown by enhanced apomorphine-induced stereotypy, elevated Bmax for specific 3H-spiperone and 3H-NPA binding, and an increase in striatal acetylcholine content. D-1 receptor sites appeared unaffected, since dopamine-stimulated adenylate cyclase and specific 3H-piflutixol binding were not altered. In contrast, neither sulpiride nor clozapine enhanced apomorphine-induced stereotypy or increased Bmax for 3H-spiperone binding. Sulpiride, but not clozapine, increased Bmax for 3H-NPA binding; clozapine, but not sulpiride, elevated striatal acetyl choline concentrations. In general, both sulpiride and clozapine enhanced D-1 function as assessed by dopamine-stimulated adenylate cyclase or 3H-piflutixol binding. On acute administration sulpiride and clozapine appear to act at D-2 sites, but continuous chronic administration of these compounds does not result in the development of striatal D-2 receptor hypersensitivity. The absence of change in D-2 function during chronic treatment, coupled with an ability to enhance D-1 function, may contribute to the low incidence of tardive dyskinesia produced by these drugs in man.
...
PMID:Differential alteration of striatal D-1 and D-2 receptors induced by the long-term administration of haloperidol, sulpiride or clozapine to rats. 315 9

The effects of a range of dopamine (DA) agonists on stereotyped behaviour in rats were analysed and compared both with the affinity of the compounds for D1 and D2 receptor binding sites in vitro and their ability to stimulate the adenylate cyclase activity in rat striatal homogenates. Full and partial agonists at the D1 receptor coupled to adenylate cyclase do not induce sterotypies when given alone, whereas full D2 agonists (e.g. quinpirole) induce hyperactivity but not oral sterotypies. Partial D2 agonists (e.g. (-)-3-PPP) only induce sedation. Mixed D1/D2 agonists (e.g. apomorphine) induce both hyperactivity and oral stereotypies. Maximum stereotypies were induced by combination of SK & F 38393 and a series of D2 agonists, including full agonists and the partial D2 agonist B-HT 920, whereas partial agonists with low intrinsic activity (e.g. (-)-3-PPP, EMD 23448) did not induce stereotypies when given together with SK & F 38393. However, these partial agonists reduced the maximum effect of apomorphine, whereas the full agonists (e.g. quinpirole, (-)-NPA) and B-HT 920 had no apomorphine antagonistic activity. The mixed D1/D2 agonists apomorphine and N,N-dipropyl-5,6-ADTN were only weakly influenced by SK & F 38393, or not at all. D1 agonists with central effects, including SK & F 38393, SK & F 81297 (with relatively high efficacies), and the partial agonist SK & F 75670 with low efficacy, changed the hyperactivity induced by quinpirole into maximum oral stereotypy, whereas the peripheral D1 agonist fenoldopam had no such effect. Inhibition of DA and NA synthesis with alpha-methyl-p-tyrosine depleted striatal DA levels by 72 per cent and antagonized the hyperactivity induced by the D2 agonists quinpirole and (-)-NPA, but not that of apomorphine. Combination of SK & F 38393 and quinpirole induced maximum stereotypy in DA-depleted animals. These results suggest that D1 receptor tonus is a necessary prerequisite for the expression of a DA agonist's effect. The hyperactivity induced by full D2 agonists appears to be mediated by D1 tonus provided by endogenous DA activity, but stronger D1 stimulation is necessary to induce oral stereotypy. A high degree of D1 receptor activation increases the ability of partial D2 agonists to induce hyperactivity or oral stereotypies since treatment with both SK & F 38393 and B-HT 920 had marked effects while B-HT 920 was ineffective.(ABSTRACT TRUNCATED AT 400 WORDS)
...
PMID:Relative dopamine D1 and D2 receptor affinity and efficacy determine whether dopamine agonists induce hyperactivity or oral stereotypy in rats. 325 94

6-Methylamino-4,5,6,7-tetrahydrobenzothiazole monochlorhydrate (14.839JL) is a new, potent dopaminergic agonist. The stereotypy induced by this drug was greater than that induced by an equivalent dose of apomorphine, was antagonized by pretreatment with sulpiride and counteracted the hypomotility induced by reserpine. Striatal levels of the dopamine metabolites homovanillic acid (HVA), dihydroxyphenylacetic acid (DOPAC) and 3-methoxytyramine (3-MT) were significantly lowered for up to 4-6 h by doses from 0.05 to 1 mg/kg. The drug was also very effective in lowering prolactine secretion. 14.839JL displaced [3H]N-n-propylnorapomorphine [3H]NPA from striatal binding sites with an IC50 similar to dopamine (DA). Conversely, the ability of 14.839JL to displace 3H spiperone from its binding sites was 100 and 10 times lower than that of haloperidol and sulpiride, and similar to that of SCH 23390. Differently from the latter, however, 14.839JL did not modify adenylate cyclase activity. All these data suggest that 14.839JL is a new, potent, long-lasting direct DA agonist, probably acting on D2 receptors.
...
PMID:Behavioural and biochemical studies on 6-methylamino-4,5,6,7-tetrahydrobenzothiazole (14.839JL), a new potent dopaminergic agonist. 343 22

Comparison has been made of the effects on brain dopamine function of chronic administration of haloperidol or clozapine to rats for up to 12 months. In rats treated for 1-12 months with haloperidol (1.4-1.6 mg/kg/day), purposeless chewing jaw movements emerged. These movements were only observed after 12 months' treatment with clozapine (24-27 mg/kg/day). Apomorphine-induced (0.125-0.25 mg/kg) stereotyped behaviour was inhibited during 12 months treatment with haloperidol. Clozapine treatment was without effect. After 12 months, stereotypy induced by higher doses of apomorphine (0.5-1.0 mg/kg) was enhanced in haloperidol, but not clozapine, treated rats. Bmax for striatal 3H-spiperone binding was elevated throughout 12 months of haloperidol administration, but was not altered by clozapine treatment. Bmax for striatal 3H-NPA binding was only elevated after 12 months of haloperidol treatment; clozapine treatment was without effect. Bmax for 3H-piflutixol binding was not altered by haloperidol treatment, but was increased after 9 and 12 months of clozapine treatment. Dopamine (50 microM)-stimulated adenylate cyclase activity was inhibited after 1 month's haloperidol treatment but normal thereafter. Adenylate cyclase activity was not altered by chronic clozapine treatment. Striatal acetylcholine content was increased after 3 and 12 months of haloperidol or clozapine intake. These findings indicate that the chronic administration of the atypical neuroleptic clozapine does not produce changes in brain dopamine function which mirror those of the typical neuroleptic haloperidol. In particular, chronic administration of clozapine, unlike haloperidol, does not appear to induce striatal D-2 receptor supersensitivity. Unexpectedly, clozapine treatment, unlike haloperidol, altered D-1 receptor function.
...
PMID:Chronic treatment with clozapine, unlike haloperidol, does not induce changes in striatal D-2 receptor function in the rat. 404 Mar 70

The D-2 dopamine receptor mediates inhibition of adenylate cyclase in rat intermediate lobe; this receptor is linked to cyclase by the inhibitory guanyl nucleotide-binding protein (Ni). The functioning of components in the inhibitory system was compared in control and pertussis toxin-treated tissues. (-)-N-n-Propylnorapomorphine ((-)-NPA), a dopamine agonist, and 5'-guanylyl imidodiphosphate (Gpp(NH)p), a nonhydrolyzable GTP analog, caused a dose-dependent inhibition of adenylate cyclase in control tissue. Pertussis toxin abolished dopamine receptor-mediated inhibition of adenylate cyclase but did not alter Gpp(NH)p-induced inhibition of cyclase. In control tissue, GTP blocked Gpp(NH)p inhibition of cyclase in the absence, but not in the presence of (-)-NPA. Following pertussis toxin treatment, GTP blocked the inhibitory effect of Gpp(NH)p either in the absence or in the presence of (-)-NPA. Pertussis toxin did not alter the number of dopamine receptors or the affinity of the receptor for [3H]spiroperidol, a dopamine antagonist. However, pertussis toxin decreased the potency of (-)-NPA in the binding assay and abolished the ability of GTP to affect agonist binding. Furthermore, pertussis toxin abolished the dopamine receptor-mediated inhibition of immunoreactive alpha-melanocyte-stimulating hormone release, and induced the ADP-ribosylation of the Mr = 41,000 subunit of Ni.
...
PMID:Altered activity of the inhibitory guanyl nucleotide-binding component (Ni) induced by pertussis toxin. Uncoupling of Ni from receptor with continued coupling of Ni to the catalytic unit. 608 7

[3H]N-propylapomorphine ([3H]NPA) a dopaminergic catecholamine derivative, labels a sub-set of D2-dopamine receptors in bovine caudate particulate preparation. [3H]Spiperone, a dopamine receptor antagonist, labels twice as many sites as [3H]NPA. Dopaminergic ergots and potent neuroleptics compete for both radioactive ligands with similar high affinities. Catecholamines and catecholamine derivatives compete more potently for [3H]NPA binding than for [3H]spiperone binding. Guanyl nucleotides reduce both [3H]NPA binding and the high affinity phase of catecholamine and catecholamine derivative competition for [3H]spiperone binding. These results are similar to binding results reported in studies of two-state receptors linked to adenylate cyclase such as the beta-adrenergic receptors. These observations indicate that the D2-dopamine receptor in the brain may exist in two states and may be inversely coupled to brain adenylate cyclase activity.
...
PMID:[3H]N-propylapomorphine and [3H]spiperone binding in brain indicate two states of the D2-dopamine receptor. 612 76


1 2 Next >>

---