Adenylate cyclase stimulants

Colforsin a diterpine directly stimulates adenylate cyclase or a structurally related protein. This causes an elevation of cAMP levels in the myocardium thereby activating the protein kinases and 

Colforsin Syn Boforsin Forskolin Forscolin ] exerts its action by causing stimulation of adenylate eyelase. It has been observed that the drug possesses positive inotropie and bronchodilator effects. 

After the spectacular revelation of amrinone s inotropic action a vigorous global effort was made in seareh of other nonsteroidal inotropic drugs. These drugs seem to enhanee the effect of existing Ca levels and subsequently eause an inotropic effect. 

A few typieal examples are diseussed here, namely Pimobendan Sulmazole  

5-Dihydro-6 [2-(p-methoxyphenyl)-5-benzimidazolyl]-5-methyl-3(2H)-pyridazinone It is found to increase the Na sensitivity of myoeardial contraetile proteins. 

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Amidines. After the initial observation that formamidines are agonists for OA receptors in the firefly (14,15 58), these compounds have been shown to mimic OA in virtually every insect system known to contain OA receptors, including the DUMETi system (59)f the glandular lobe of the corpus cardiacum (60) and the fat body ( ) of the locust, and various CNS adenylate cyclase preparations (26-28). The structure-activity relations of amidines as octopaminergic agonists have been examined in several systems including adenylate cyclase stimulation in the firefly lantern and... 

Active site, model, 308f Adenylate cyclase stimulation, 118 substituted-phenyl... 

The second-messenger linkage of postsynaptic 5-HTj receptors has been connected in various neurons with either inhibition of adenylate cyclase, stimulation of adenylate cyclase, or inhibition of phosphoinositide turnover (Harrington et al. 1992]. 

Rm did not correlate with the intrinsic activity of agonists for their ability to attenuate adenylate cyclase stimulation (36).In that system, only the ratio of K./K appeared to correlate with the intrinsic activity ofLthe alpha-adrenergic agonists. Here, in anterior pituitary membranes constant proportions of both receptor states were evidenced but ratios of 30-200 were found for K./Km for a series of dopaminergic agonists despite the fact that these agonists all appear to display full intrinsic activity in their ability to inhibit prolactin secretion from pituitary cells. 

A very intriguing observation noted above was the possibility of presynaptic dopamine agonist activity with SK F 87516 and SK F 85174. The inhibitions of the constrictor response and the 3H -norepinephrine release induced by brief intermittent periarterial sympathetic nerve stimulation of the perfused rabbit ear artery is a convenient in vitro assay for presynaptic dopamine agonist activity (30). In this preparation, both SK F 85174 and SK F 87516 inhibited both stimulation responses with an EC50 of about 100 riM. Another measure of D-2 activity is inhibition of specific spiroperidol binding (20). Comparison of these data (Table I) showed that SK F 85174 is thirty times as potent as dopamine, and thus is a potent D-2 agonist. However, the activity in adenylate cyclase stimulation indicates that this compound may be best described as a D-l/D-2 agonist (19, 20). 

Adham N, Zgombick JM, Bard J, Branchek TA. Functional characterization of the recombinant human 5-hydroxytiyptamine7(a) receptor isoform coupled to adenylate cyclase stimulation. J Pharmacol Exp Ther 1998 287 508-514. 

Bristow, M. R., Cubicciotti, R., Ginsburg, R., Stinson, E. B., and Johnson, C. 1982. Histamine-mediated adenylate cyclase stimulation in human myocardium. Mol. Pharmacol. 21 671-679. 

Bristow MR, Hershberger RE, Port JD, Minobe W, Rasmussen R. pr Adrenergic and p2-adrenergic receptor-mediated adenylate-cyclase stimulation in nonfailing and failing human ventricular myocardium. MolPharmacol 1989 35 295-303. 

Since the effect of TSH on TPMP+ uptake precedes the effect of the hormone on adenylate cyclase activity,1 7 the possibility exists that a primary mode of action of each of these effectors is to alter electrochemical ion gradients across the cell membrane. This concept is attractive in that it would serve to explain certain other findings. Thus, hCG causes changes in adrenal cell ion transport which not only precede adenylate cyclase stimulation, but occur at concentrations of the effector which have minimal effects on cyclase activity 1 9 cholera toxin and its B protein induce alterations in the permeability of liposomes reconstituted with "receptor" ganglioside in the absence of adenylate cyclase.50 51... 

C. Reithmann, P. Gierschik, D. Siiii-ROPOULOS, K. Werdan, and K. H. Jakobs, Mechanism of noradrenaline-induced heterologous desensitization of adenylate cyclase stimulation in rat heart muscle cells increase in the level of inhibitory G-protein alpha-subunits, Eur. J. Pharmacol., 1989, 272, 211-221. 

The PGE2-activated prostanoid receptors on DRG neurons (EPj, EP4, and some splice variants of EP3 receptors — EP3B and EP3( ) can be coupled to the stimulation of adenylate cyclase to raise cAMP levels. Experimental elevation of cAMP with the adenylate cyclase stimulator, forskolin, or application of membrane permeant cAMP analogues, dibutyryl cAMP (dbcAMP) and 8-bromo-cAMP, mimicked the effect of PGE2 treatment by shifting the activation... 

A first glimpse to the interaction of the main classes of dopaminergic agonists and antagonists with the new subtypes is provided by the extensive tabulation of affinity data reported by Seeman and van Tol [43], some of which are shown in Table 1. No selectivity was detected between Dj and D5 in these studies, but an over-simplified description of the family appears undue. For instance, the selective benzazepine SK F 83959 els ) showed high affinity, to variable action (from weakly agonistic to antagonistic) on adenylate cyclase stimulation in Dj receptor preparations from different brain areas, and still potently induced Di.iike behavioural effects in laboratory animals [44, 45]. 

Schlesinger, D. H., Goldstein, G., and NiaU, H. D. (1975). The complete amino acid sequence of ubiquitin, an adenylate cyclase stimulating polypeptide probably universal in living cells. Biochemistry 14, 2214—2218. 

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