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)

[3-Iodo-Tyr2]oxytocin (MIOT), [3,5-diiodo-Tyr2]oxytocin (DIOT), [3-iodo-Tyr2,Lys8]vasopressin (MILVP), [3,5-diiodo-Tyr2,Lys8]vasopressin (DILVP), [3-iodo-Tyr2,Arg8]vasopressin (MIAVP), and [3,5-diiodo-Tyr2,Arg8]vasopressin (DIAVP) were synthesized by iodination of the respective hormones, pruified, and characterized. All the monoiodo hormones had to be freshly prepared prior to bioassays, since on storage they gave rise to hormonal-like biological activity. The biological activities of these iodo analogues were measured in an adenylate cyclase assay employing neurohypophyseal hormone (NHH) sensitive bovine renal medullary membranes, and/or the rat oxytocic assay. In the cyclase assay, DIOT, DILVP, and DIAVP were inactive as agonists or antagonists. MIOT shows no agonistic activity in the renal cyclase system and uterus, but is a weak reversible inhibitor of oxytocin (OT) in both systems. When MIOT (10(-4) M) was preincubated with renal membranes for 10 min at 37 degrees C before addition of OT, it behaved as a noncompetitive inhibitor of NHH-stimulated adenylate cyclase. MILVP and MIAVP appear to be partial agonists with Km (half maximal response) 3 X 10(-6) and 3 X 10(-7) M, respectively, as determined in the cyclase assay. Upon preincubation with renal medullary membranes, MILVP (10(-6) M) behaves as a more potent noncompetitive inhibitor of OT than MIOT. Accordingly, iodo derivatives of NHH do not exhibit sufficient affinity to serve an specific ligands to measure OT, LVP, or AVP receptors in the uterus and kidney. Study of the specificity of inhibition produced by MIOT revealed that this analogue does not act selectively upon NHH receptors. Thus, MIOT modified adenylate cyclase systems which do not have NHH receptors, e.g., the PTH-sensitive adenylate cyclase in bovine renal cortex and the glucagon-sensitive adenylate cyclase in rat liver. DIOT, DILVP, and DIAVP were subjected to catalytic tritiation (employing carrier free tritium) and were converted to [3H]OT (25, 31, and 25 Ci/mmol), [3H]LVP (26 and 23 Ci/mmol), and [3H]AVP (17 Ci/mmol), respectively. These tritiated ligands have been successfully used to measure NHH receptor sites both in kidney and uterine membranes as described in other studies.
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PMID:Iodinated neurohypophyseal hormones as potential ligands for receptor binding and intermediates in synthesis of tritiated hormones. 19 53

A novel photoreactive calmodulin (CaM) derivative was developed and used to label the purified CaM-sensitive adenylate cyclase from bovine cortex. 125I-CaM was conjugated with the heterobifunctional cross-linking agent p-nitrophenyl 3-diazopyruvate (DAPpNP). Spectral data indicated that diazopyruvoyl (DAP) groups were incorporated into the CaM molecule. Iodo-CaM-DAPs behaved like native CaM with respect to (1) Ca2+-dependent enhanced mobility on sodium dodecyl sulfate-polyacrylamide gels and (2) Ca2+-dependent stimulation of adenylate cyclase activity. 125I-CaM-DAP photochemically cross-linked to CaM-binding proteins in a manner that was both Ca2+ dependent and CaM specific. Photolysis of forskolin-agarose-purified adenylate cyclase from bovine cortex with 125I-CaM-DAP produced a single cross-linked product which migrates on sodium dodecyl sulfate-polyacrylamide gels with an apparent molecular weight of approximately 140,000.
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PMID:Development of a novel photoreactive calmodulin derivative: cross-linking of purified adenylate cyclase from bovine brain. 277 48

Specific [125I]-Iodo-NTyr somatostatin binding sites are present in adenohypophyseal and cerebral cortical membranes. Guanine nucleotides reduce the maximal binding capacity of adenohypophyseal binding sites without significantly affecting their apparent affinity. In pituitary as well as in cortex, GTP is the most potent nucleotide followed by GDP and guanylyl imidodiphosphate (GMP-PNP). The effect appears specific of guanine nucleotides since ATP, ADP and AMP are inactive on [125I]-Iodo-NTyr somatostatin binding. These results, showing the nucleotide sensitivity of [125I]-Iodo-NTyr somatostatin binding in pituitary and cerebral cortex, are compatible with a coupling of somatostatin receptors with adenylate cyclase.
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PMID:Guanine nucleotide sensitivity of [125I]-Iodo NTyr somatostatin binding in rat adenohypophysis and cerebral cortex. 613 1

Two subtypes of the mammalian cannabinoid receptor have been identified and successfully cloned since 1990. The CB(1) receptor is primarily located in the central nervous system and the CB(2) receptor is almost exclusively expressed in cells of the immune system. The CB(1) and CB(2) receptors are both G-protein coupled receptors and are involved in the inhibition of adenylate cyclase. The CB(2) receptor is of particular importance due to its involvement in signal transduction in the immune system, making it a potential target for therapeutic immune intervention. A number of these selective ligands are derivatives of traditional dibenzopyran based cannabinoids. These include the very recently synthesized (2'R)-1-methoxy-3-(2'-methylbutyl)- Delta (8)-THC (JWH-359) which has a 224 fold selectivity for the CB(2) receptor, readily comparable to the well known 1-deoxy-3-(1',1'-dimethylbutyl)- Delta (8)-THC (JWH-133) which has 200 fold selectivity for the CB(2) receptor. Several 9-hydroxyhexahydrocannabinols have also been synthesized and are found to be selective high affinity ligands for the CB(2) receptor. These are 1-deoxy-9beta-hydroxy-dimethylhexylhexahydrocannabinol (JWH-361, K(i) = 2.7 nM) and 1-deoxy-9beta-hydroxy-dimethylpentylhexahydrocannabinol (JWH-300, K(i) = 5.3 nM). CB(2) selective cannabi-mimetic indoles include 1-(2,3-dichlorobenzoyl)-2-methyl-3-(2-[1-morpholine]ethyl)-5-methoxyindole (L768242), (R)-3-(2-Iodo-5-nitrobenzoyl)-1-(1-methyl-2-piperidinylmethyl)-1H-indole (AM1241) and 1-propyl-2-methyl-3-(1-naphthoyl) indole (JWH-015), which exhibit significant selectivity for the CB(2) receptor coupled with weak affinity for the CB(1) receptor. Bristol-Meyer Squibb has produced a phenylalanine derived cannabimimetic indole which possesses high CB(2) affinity (K(i) = 8 nM) and very low affinity for the CB(1) receptor (K(i) = 4000 nM). This review will discuss the current advances and recent results in the structure-activity relationships (SAR) of selective ligands for the cannabinoid CB(2) receptor.
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PMID:Recent advances in the development of selective ligands for the cannabinoid CB(2) receptor. 1828 88