Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Two aspects of the complexities of the mode of action of drugs are described. One is the criteria and pitfalls of defining the interaction with specific receptors. The other is the need to consider each of the pharmacological effects of a drug as a concatenation of receptor events, because it has become clear that each drug may have substantial affinity for many specific receptors. Illustrating these ideas is a characterization of the histamine receptor linked to adenylate cyclase in brain. The activities of a series of H2-antagonists and H2-agaonists were shown to be the same on the histamine receptor linked to adenylate cyclase as on known H2-receptors. The KB values of antagonists and ED50 values of agonists were not distinguishable among these receptors. Notably, at high concentrations, the H1-antagonists are also competitive antagonists of the H2-receptor. Cyproheptadine has especially high affinity for the H2-receptor. It is the most potent H2-antagonist yet reported. Other published results are reviewed to show the variety of receptors that cyproheptadine has affinity for. Its affinity for serotonin receptors led us to examine other serotonin antagonists. On this H2-receptor linked to adenylate cyclase in homogenates of guinea pig hippocampus and cortex, D-LSD and D-2-bromo-LSD (BrLSD) were shown to be competitive antagonists of histamine. L-LSD, mescaline and psilocin were inactive. Noting congurency in the molecular structyre of D-LSD and known H2-antagonists, we predicted a new H2-antagonist. This prediction is shown to be correct: the compound has similar affinity to the H2-receptor as has LSD. The affinities of D-LSD and BrLSD for the H2-receptor are compared with their affinities for other receptors. The pharmacology of D-LSD and BrLSD is reviewed. Evidence is assembled that BrLSD has considerable central effects.
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PMID:Defining the histamine H2-receptor in brain: the interaction with LSD. 3 Sep 11

The characteristics of dopamine, 1-isoproterenol, and d-LSD stimulated adenylate cyclases were studied in homogenates of fresh or frozen tissues. In rat striatum, when the assay was done in the presence of 1 mM MgSO4, dopamine (10(-4) M) stimulated the enzyme activity by 3.5-fold. This effect was completely blocked by fluphenazine (10(-5) M; Ki = 9 X 10(-9) M) and by phentolamine (Ki = 3 X 10(-7) M). d-LSD stimulated the adenylate cyclase activity (Km = 1.4 X 10(-7) M) by interacting with the dopaminergic receptors. Maximal adenylate cyclase stimulation by d-LSD was 1.4-fold; as a matter of fact, this compound acted as a partial agonist on the dopaminergic receptors. l-Isoproterenol (Km = 10(-6) M) activated an adenylate cyclase present in rat striatum homogenates through a receptor distinct from the dopaminergic receptor; this stimulation was not affected by addition of fluphenazine or phentolamine but suppressed by dl-propranolol (10(-4) M). The topographical distributions of dopamine adenylate cyclase activity and endogeneous dopamine content were examined in homogenates prepared from discs punched out from serial frozen (-7 degrees C) slices of the striatum. A 4.8-fold progressive decrease in the amount of cyclic AMP produced in the presence of dopamine (10(-4) M) was observed from the rostral to the caudal part of the structure. The d-LSD-sensitive adenylate cyclase followed a similar distribution. It should be noted that the topographic distribution of endogeneous dopamine is quite comparable to the distribution of the dopamine-sensitive adenylate cyclase, suggesting that this enzyme is an integral part of the dopamine synapses. We also reported that the frontal cortex contains a dopamine-sensitive adenylate cyclase. In conclusion, we trust that the micromethod described for adenylate cyclase assay will be of some use in the study of the precise topographic distribution of catecholamine sensitive adenylate cyclases in different structures of brain.
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PMID:Repartition and drug sensitivity of dopamine and L-isoproterenol-sensitive adenylate cyclases in rat brain homogenates. 19 54

The influence of haloperidol and propranolol on aggressiveness, motility exploration and general behavior, and the activity or level of adenylate cyclase, cyclic AMP, and protein kinase in the brain of mice treated with LSD was tested. Haloperidol evidently, and propranolol slightly less, inhibited the behavioral and biochemical changes induced by LSD. It is suggested that psychotomimetic effects of LSD depend on complex action of this compound on aminergic receptors in the central nervous system, and the antipsychotic effectiveness of haloperidol and propranolol is related to interaction of these drugs and LSD with the receptors for monoamines participating in the central neuromediation.
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PMID:The influence of haloperidol and propranolol on behavior and biochemical changes in the brain of mice treated with LSD. 19 69

Investigations were carried out on the interactions of the hallucinogenic drug, D-lysergic acid diethylamide (D-LSD), and other serotonin antagonists with catecholamine-sensitive adenylate cyclase systems in cell-free preparations from different regions of rat brain. In equimolar concentration, D-LSD, 2-brono-D-lysergic acid diethylamide (BOL), or methysergide (UML) strongly blocked maximal stimulation of adenylate cyclase activity by either norepinephrine or dopamine in particulate preparations from cerebral cortices of young adult rats. D-LSD also eliminated the stimulation of adenylate cyclase activity of equimolar concentrations of norepinephrine or dopamine in particulate preparations from rat hippocampus. The effects of this hallucinogenic agent on adenylate cyclase activity were most striking in particulate preparations from corpus striatum. Thus, in 10 muM concentration, D-LSD not only completely eradicated the response to 10 muM dopamine in these preparations but also consistently stimulated adenylate cyclase activity. L-LSD (80 muM) was without effect. Significant activation of striatal adenylate cyclase was produced by 0.1 muM D-LSD. Activation of striatal adenylate cyclase of either D-LSD or dopamine was strongly blocked by the dopamine-blocking agents trifluoperazine, thioridazine, chlorpromazine, and haloperidol. The stimulatory effects of D-LSD and dopamine were also inhibited by the serotonin-blocking agents, BOL, 1-methyl-D-lysergic acid diethylamide (MLD), and cyproheptadine, but not by the beta-adrenergic-blocking agent, propranolol. However, these serotonin antagonists by themselves were incapable of stimulating adenylate cyclase activity in the striatal preparations. Several other hallucinogens, which were structurally related to serotonin, were also inactive in this regard, e.g., mescaline, N,N-dimethyltryptamine, psilocin and bufotenine. Serotonin itself produced a small stimulation of adenylate cyclase activity in striatal preparations and, in relatively high concentration (100 muM), partially blocked the activation by 10 muM dopamine, but was without effect on the stimulation by 10 muM D-LSD. The present results indicate that serotonin antagonists, in general, are potent inhibitors of catecholamine-induced stimulation of adenylate cyclase systems in brain cell-free preparations. In addition, these results, coupled with earlier findings on the capacity of D-LSD to interact with serotonin-sensitive adenylate cyclase systems from rat brain23,24 and other neural systems16, strongly suggest that this hallucinogenic agent is capable of acting as an agonist at central dopamine and serotonin receptors, as well as functioning as an antagonist at dopamine, norepinephrine, and serotonin receptors in the brain.
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PMID:Interactions between lysergic acid diethylamide and dopamine-sensitive adenylate cyclase systems in rat brain. 23 21

Dopamine receptors in the central nervous system can be studied by measuring the specific binding of [3H]dopamine, [3H]haloperidol, d-[3H]LSD, [3H]dihydroergocryptine or [3H]apomorphine. The receptors are stereoselectively blocked by +)-butaclamol, a neuroleptic. All neuroleptics inhibit the specific binding of [3H]haloperidol in relation to their clinical potencies. The radioligand that desorbs most slowly from the receptor is [3H]apomorphine, thus making it a reliable ligand for dopamine receptors. Dopamine agonists that compete for [3H]apomorphine binding do so at concentrations that correlate with their potency in stimulating striatal adenylate cyclase. Structure-activity analysis, using [3H]apomorphine, confirms that the active dopamine-mimetic conformation is the beta rotamer of dopamine. Prolonged exposure in vitro of caudate homogenate to high concentrations of dopamine leads to increased binding of [3H]apomorphine or [3H]haloperidol, suggesting receptor "sensitization." Chronic haloperidol treatment of rats leads to an increased number of dopamine/neuroleptic receptors in the striatum, but a decrease in the pituitary.
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PMID:Dopamine receptors in the central nervous system. 41 36

The dopamine (DA)-receptor mediated changes in striatal acetylcholine (ACh) levels have been studied to determine if this effect involves a D1-(adenylate cyclase dependent) or D2-(not linked to an adenylate cyclase) type of DA-receptor, Various DA-agonists (apomorphine, N-diphenethylamine derivatives) increased striatal ACh levels in both intact and 6-OHDA lesioned rats whereas only apomorphine stimulated the adenylate cyclase activity of striatal homogenates. The N-diphenethylamine compounds (RU 24213, RU 24926 and RU 26933) were without effect either on basal or DA-stimulated activities of this enzyme. In contrast, D-LSD (which acts as a partial agonist of the striatal DA-sensitive adenylate cyclase) did not modify the striatal ACh content. More interestingly, an intrastriatal injection of cholera toxin greatly stimulated striatal adenylate cyclase without altering ACh concentrations. Both haloperidol and methergoline antagonized the DA stimulation of adenylate cyclase, but only haloperidol decreased striatal ACh levels. These results indicate that the DA receptor involved in regulating the activity of striatal cholinergic neurons is of the D2-type.
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PMID:Is dopamine-sensitive adenylate cyclase involved in regulating the activity of striatal cholinergic neurons? 53 Mar 5

Since quipazine is a potent 5-HT agonist in peripheral organs, its possible stimulatory effects on serotoninergic receptors in the rat brain were investigated. Quipazine administration (10 mg/kg, i.p.) induced a significant decrease in the synthesis and turnover rates of serotonin in the brain stem as well as in the forebrain. It is not likely that these changes were mediated by a negative feed-back mechanism triggered by a direct action of quipazine on central 5-HT postsynaptic receptors. Indeed, in contrast to LSD and 5-methoxy-N,N-dimethyltryptamine, this compound failed to activate the 5-HT sensitive adenylate cyclase in colliculi homogenates of newborn rats. However, quipazine exerted direct effects on serotoninergic terminals. It inhibited competitively the reuptake process in synaptosomes (Ki=1.38 X 10(-7) M) and stimulated the K+ evoked release of newly synthesized 3H-5-HT in slices of the brain stem. Injected in vivo in a dose which affected 5-HT uptake and release, quipazine did not modify MAO activity. However, this activity was non-competitively inhibited by high concentratin of the drug in vitro (Ki=3.0 X 10(-5) M). These actions are very likely indirectly responsible for the stimulation of central 5-HT receptors.
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PMID:The effects of quipazine on 5-HT metabolism in the rat brain. 100 32

Cell-free preparations from superior and inferior colliculi of very young rats (1-3 days old) contained adenylate cyclase systems which were highly responsive to serotonin. The response to serotonin declined markedly during early development and was very low at maturity. Adenylate cyclase activity in the 10,000 times g particulate fraction from colliculi of newborn rats was significantly stimulated by 0.05 muM serotonin. Half-maximal activation was produced with less than 1 muM serotonin. Maximal stimulation of collicular adenylate cyclase was about 80% above basal enzyme activity and occurred with approximately 50 muM serotonin. Tryptamine and several derivatives of serotonin produced responses which were comparable to that obtained with serotonin; 5-methoxytryptamine was uniformly the most active compound tested. Norepinephrine or dopamine produced much smaller increases in adenylate cyclase activity. Stimulation of collicular adenylate cyclase by serotonin was significantly but incompletely blocked by serotonin antagonists, including d-lysergic acid diethylamide (d-LSD), 2-bromo-d-lysergic acid diethylamide, methysergide, 1-methyl-8 beta-carbobenzyloxy-aminomethyl-10 alpha-ergoline and cyproheptadine. Chlorpromazine also produced partial blockade. In contrast, l-lysergic acid diethylamide, haloperidol, propranolol, phenoxybenzamine and morphine were ineffective as serotonin blocking agents. Of the compounds which produced a partial blockage of serotonin action, d-LSD, cyproheptadine and chlorpromazine were themselves capable of stimulating adenylate cyclase activity. These results are consisent with the existence of multiple receptors in rat brain which are capable of interacting with indoleamines.
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PMID:Serotonin-sensitive adenylate cyclase activity of immature rat brain. 107 37

The characteristics of dopamine adenylate cyclase in the rat striatum were first studied on homogenates of fresh tissues. In the assay conditions used, dopamine (10(-4) M) stimulated the enzyme activity by 250%. This effect was completely blocked by fluphenazine (10(-5) M; Ki=9X10(-9) M) and by phentolamine (10(-5) M; Ki=3 X 10(-7) M). D-LSD stimulated the adenylate cyclase activity (Km=1.4 X 10(-7) M) by interacting with dopamine receptors; indeed the dopamine effect on the enzyme activity was competitively reduced in presence of D-LSD. L-Isoproterenol (Km=10(-6) M) activated an adenylate cyclase through a receptor distinct form the dopaminergic receptor; this stimulation was not affected by fluphenazine or phentolamine but suppressed by DL-propranolol (10(-4) M). The topographical distribution of the dopamine, D-LSD and L-isoproterenol adenylate cyclase activities were examined in homogenates prepared from discs punched out on serial frozed (--7C) slices of the striatum. Under this condition, tge dioanube naxunak stunykatuib was if 150%. A 4.8-fold progressive decrease in the amount of cyclic AMP produced in presence of dopamine (10(-4) M) was observed in the rostrocaudal plane of the structure; the decline of the basal activity was 3.6-fold. The topographical curves of maximal activation of adenylate cyclase by dopamine and D-LSD were superimposable confirming that D-LSD acts on dopaminergic receptors. This topographical distribution of dopamine sensitive adenylate cyclase is comparable on one hand to that of endogenous dopamine and on the other hand to that of the dopamine high affinity uptake activity measured in simultaneous experiments. In contrast to that observed with dopamine or D-LSD, the topographical distribution of the adenylate cyclase sensitive to L-isoproterenol was homogenous within the striatum.
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PMID:Topographical distribution of dopaminergic innervation and of dopaminergic receptors in the rat striatum. II. Distribution and characteristics of dopamine adenylate cyclase--interaction of d-LSD with dopaminergic receptors. 126 30

Serotonin (5-HT) is a neuromodulator that mediates a wide range of physiological functions by activating multiple receptors. Using a strategy based on amino acid sequence homology between 5-HT receptors that interact with G proteins, we have isolated a cDNA encoding a new serotonin receptor from a mouse brain library. Amino acid sequence comparisons revealed that this receptor was a distant relative of all previously identified 5-HT receptors; we therefore named it 5HT5. When expressed in Cos-7 cells and NIH-3T3 cells, the 5HT5 receptor displayed a high affinity for the serotonergic radioligand [125I]LSD. Surprisingly, its pharmacological profile resembled that of the 5HT1D receptor, which is a 5-HT receptor subtype which has been shown to inhibit adenylate cyclase and which is predominantly expressed in basal ganglia. However, unlike 5HT1D receptors, the 5HT5 receptor did not inhibit adenylate cyclase and its mRNA was not found in basal ganglia. On the contrary, in situ hybridization experiments revealed that the 5HT5 mRNA was expressed predominantly in cerebral cortex, hippocampus, habenula, olfactory bulb and granular layer of the cerebellum. Our results therefore demonstrate that the 5HT1D receptors constitute a heterogeneous family of receptors with distinct intracellular signalling properties and expression patterns.
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PMID:The mouse 5HT5 receptor reveals a remarkable heterogeneity within the 5HT1D receptor family. 146 8


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