MDL 12330A hydrochloride

IC50: 1.5 X 10-5 M for histamine-stimulated adenylate cyclase [1].

RMI 12330 A is N,-(cis-2-phenylcyclopentyl) azacyclotridecan-2-imine hydrochloride, which has been reported to inhibit choleratoxin-induced intestinal hypersecretion, presumably via an inhibition of mucosal adenylate cyclase.

In vitro: RMI 12330 A at the concentration of ranging from 10 uM to 5 mM the can effectively inhibit the adenylate cyclase activity of a rat liver plasma membrane preparation. RMI 12330 A does not apply its competition on the catalytic site of the enzyme to perform its inhibitory action. The inhibition activity of RMI 12330 A upon adenylate cyclase was due to an irreversible binding with the plasma membranes [2].

Ex vivo: In the isolated work-performing heart of the guinea-pig, RMI 12330A depressed all cardiac functions with the IC50 of 1.1 X 10-6 M, including contractile force, dP/dt, dF/dt, pressures developed, stroke work and work performance. The positive inotropic response to increasing heart rate (staircase) and left atrial pressure rose became negative. Ouabain, isoprenaline and histamine, no longer had positive inotropic effects. After its depression by RMI 12330A, the cardiac function can be completely restored by increasing the perfusate calcium concentration from 2.5 mm to 4.5 and 6.5 mm [1].

Clinical trial: So far, no clinical study has been conducted.

References:
[1] Grupp G, Grupp IL, Johnson CL, Matlib MA, Rouslin W, Schwartz A, Wallick ET, Wang T, Wisler P.  Effects of RMI 12330A, a new inhibitor of adenylate cyclase on myocardial function and subcellular activity. Br J Pharmacol. 1980 Nov;70(3):429-42.
[2] Guellaen G, Mahu JL, Mavier P, Berthelot P, Hanoune J.  RMI 12330 A, an inhibitor of adenylate cyclase in rat liver. Biochim Biophys Acta. 1977 Oct 13;484(2):465-75.

Ca2+ entry mediated by store depletion, S-nitrosylation, and TRP3 channels. Comparison of coupling and function.[Pubmed:10878007]

J Biol Chem. 2000 Sep 15;275(37):28562-8.

The mechanism for coupling between Ca(2+) stores and store-operated channels (SOCs) is an important but unresolved question. SOC-mediated Ca(2+) entry is complex and may reflect more than one type of channel and coupling mechanism. To assess such possible divergence the function and coupling of SOCs was compared with two other distinct yet related Ca(2+) entry mechanisms. SOC coupling in DDT(1)MF-2 smooth muscle cells was prevented by the permeant inositol 1,4,5-trisphosphate (InsP(3)) receptor blockers, 2-aminoethoxydiphenyl borate (2-APB) and xestospongin C. In contrast, Ca(2+) entry induced by S-nitrosylation and potentiated by store depletion (Ma, H-T., Favre, C. J., Patterson, R. L., Stone, M. R., and Gill, D. L. (1999) J. Biol. Chem. 274, 35318-35324) was unaffected by 2-APB, suggesting that this entry mechanism is independent of InsP(3) receptors. The cycloalkyl lactamimide, MDL-12, 330A (MDL), prevented SOC activation (IC(50) 10 micrometer) and similarly completely blocked S-nitrosylation-mediated Ca(2+) entry. Ca(2+) entry mediated by the TRP3 channel stably expressed in HEK293 cells was activated by phospholipase C-coupled receptors but independent of Ca(2+) store depletion (Ma, H.-T., Patterson, R. L., van Rossum, D. B., Birnbaumer, L., Mikoshiba, K., and Gill, D. L. (2000) Science 287, 1647-1651). Receptor-induced TRP3 activation was 2-APB-sensitive and fully blocked by MDL. Direct stimulation of TRP3 channels by the permeant diacylglycerol derivative, 1-oleoyl-2-acetyl-sn-glycerol, was not blocked by 2-APB, but was again prevented by MDL. The results indicate that although the activation and coupling processes for each of the three entry mechanisms are distinct, sensitivity to MDL is a feature shared by all three mechanisms, suggesting there may be a common structural feature in the channels themselves or an associated regulatory component.

RMI 12330A, an inhibitor of cyclic nucleotide phosphodiesterases and adenylate cyclase in kidney preparations.[Pubmed:6256001]

Biochim Biophys Acta. 1980 Jun 13;613(2):499-506.

N-(cis-2-phenylcyclopentyl)azacyclotridecan-2-imine hydrochloride (RMI 12330A) inhibited cyclic AMP and cyclic GMP phosphodiesterase activities in kidney preparations from rat and mouse. The drug was effective in the concentration range 0.1-1 mM. The agent was much less effective in inhibiting chick kidney cyclic nucleotide phosphodiesterases. The onset of inhibition of rat particulate cyclic AMP phosphodiesterase activities was rapid (less than 30 s) and irreversible. The inhibition of the low Km forms of cyclic AMP phosphodiesterase in mouse kidney homogenates was of the non-competitive type. RMI 12330A inhibited cyclic AMP phosphodiesterase activities in intact rat renal tubules. Adenylate cyclase activity, both basal and stimulated, was inhibited in all three species by the drug. Since RMI 12330A affects cyclic GMP metabolism as well as cyclic AMP metabolism, caution must be exercised in interpreting its effects upon cellular processes in terms of its actions upon the adenylate cyclase-cyclic AMP pathway alone.

RMI 12330 A, an inhibitor of adenylate cyclase in rat liver.[Pubmed:911855]

Biochim Biophys Acta. 1977 Oct 13;484(2):465-75.

RMI 12330 A, (N,-(cis-2-phenylcyclopentyl) azacyclotridecan-2-imine hydrochloride), has been reported to inhibit choleratoxin-induced intestinal hypersecretion, presumably via an inhibition of mucosal adenylate cyclase (ATP:pyrophosphate-lyase (cyclizing), EC 4.6.1.1). We report here that the adenylate cyclase activity of a rat liver plasma membrane preparation was inhibited by concentrations of RMI 12330 A ranging from 10 muM to 5mM. Similar effects were observed when the adenylate cyclase preparation was assayed in the presence of 10 mM NaF, 0.1 muM glucagon or 1 muM (--)-epinephrine plus 10 muM GTP. The effect of RMI 12330 A was not due to the inhibition of the regenerating system present in the incubation medium, since the effect was preserved in its absence. The inhibition brought about by RMI 12330 A was due to a decrease in the maximal velocity of the reaction; the affinity of the enzyme for the substrate remained unmodified. The inhibition was immediate and irreversible, even after several washes of the membranes previously preincubated with the drug. Complete inhibition of cyclase was obtained at a concentration of 370 nmol of RMI 12330 A per mg of membrane protein. The drug acted with a similar dose-response curve upon intact as well as detergent-dispersed cyclase preparations.