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)

In recent research a new series of specific drugs, one of which is guanabenz (GBZ, 2,6(dichlorobenzyliden)-aminoguanidine) has been introduced into the clinical treatment of centrally mediated hypertension. Guanabenz (GBZ) is considered to be among the most specific alpha 2-adrenergic agonists, acting similarly to clonidine by decreasing the sympathetic outflow from the brain to the peripheral circulatory system. In the present report we show that GBZ displays a significant affinity for beta-adrenoceptors. In displacement studies of the iodinated beta-antagonist [125I]cyanopindolol (CYP) from turkey erythrocyte membranes, the dissociation constant of GBZ was 3.8 microM. Inhibition of the (-) epinephrine induced adenylate cyclase activity by GBZ is competitive, with an apparent dissociation constant of 30 microM. A similar value was obtained by studies of GBZ's effect on the (-) epinephrine-induced [3H]cAMP accumulation in intact turkey erythrocytes. In view of its unexpected affinity for beta-adrenoceptors, we examined the three-dimensional structure of crystalline GBZ. In these studies substantial differences between clonidine and GBZ were observed, despite their strong structural resemblance. These dissimilarities (angle of rotation phi = 39.7 degrees as compared to 76 degrees in clonidine, and the rotational restriction of clonidine as compared to the greater mobility in rotation of GBZ) could explain the difference of specificity between these two compounds.
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PMID:Beta-adrenergic activity and conformation of the antihypertensive specific alpha 2-agonist drug, guanabenz. 285 65

Marked differences in the characteristics of alpha-2 adrenoceptors in the kidney of various species have been reported. In addition, there are functional differences in alpha-2 adrenoceptors in various nephron segments of the same species. In this study we have characterized alpha-2 adrenoceptors in the medullary thick ascending limb (MTAL) isolated from the rabbit kidney. The equilibrium binding of [3H]rauwolscine to MTAL homogenates was measured after incubation for 45 min at 25 degrees C in the absence and presence of 10 microM phentolamine. The specific binding of [3H]rauwolscine was saturable with a Kd of 2.6 +/- 0.1 nM and maximal binding of 234 +/- 18 fmol/mg of protein. Adrenergic drugs competed with MTAL-bound [3H]rauwolscine with the following order of potency: 1) antagonists: rauwolscine = yohimbine > phentolamine >> prazosin = propranolol; and 2) agonists: oxymetazoline > clonidine > epinephrine > BHT 933 (azepexole) > alpha-methylnorepinephrine. Our results indicate that specific alpha-2 adrenoceptors are present in the rabbit MTAL. The high (> 1600) ratio of Ki of prazosin: oxymetazoline suggests that the alpha-2 adrenoceptors in the rabbit MTAL belong to an alpha-2A subtype. Guanabenz, iodoclonidine and epinephrine at high concentrations decreased forskolin- and vasopressin-stimulated cyclic AMP formation in the rabbit MTAL. These results suggest that alpha-2 adrenoceptors are negatively coupled to adenylate cyclase system in the MTAL.
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PMID:Alpha-2 adrenoceptors in medullary thick ascending limbs of the rabbit kidney. 839 54