Structure/Activity Relationships of (M)ANT- and TNP-Nucleotides for Inhibition of Rat Soluble Guanylyl Cyclase α₁β₁

Abstract

Soluble guanylyl cyclase (sGC) plays an important role in cardiovascular function and catalyzes formation of cGMP. sGC is activated by nitric oxide and allosteric stimulators and activators. However, despite its therapeutic relevance, the regulatory mechanisms of sGC are still incompletely understood. A major reason for this situation is that no crystal structures of active sGC have been resolved so far. An important step toward this goal is the identification of high-affinity ligands that stabilize an sGC conformation resembling the active, "fully closed" state. Therefore, we examined inhibition of rat sGCa 1 b 1 by 38 purine-and pyrimidinenucleotides with 2,4,6,-trinitrophenyl and (N-methyl)anthraniloyl substitutions at the ribosyl moiety and compared the data with that for the structurally related membranous adenylyl cyclases (mACs) 1, 2, 5 and the purified mAC catalytic subunits VC1:IIC2.

International Union of Basic and Clinical Pharmacology. CI. Structures and Small Molecule Modulators of Mammalian Adenylyl Cyclases

“…The potent sGC inhibition by (M)ANT-nucleotides is not surprising in light of the high conservation of the catalytic domains of these enzymes (Sunahara et al, 1998;Dove et al, 2014). Given the beneficial clinical effects of allosteric sGC activators and sGC stimulators (Stasch et al, 2011(Stasch et al, , 2015, sGC inhibition would be clearly an off-target effect of mAC inhibitors (Dove et al, 2014). However, there is evidence for pharmacological distinction between mACs and sGC with (M)ANT-and TNP-nucleotides (Dove et al, 2014) (Table 6).…”

“…In general, AC2 is the least sensitive mAC isoform toward TNP-and (M)ANTnucleotides, but selectivity for ACs 1 and 5 is at best 10-fold (Gille et al, 2004;Suryanarayana et al, 2009a;Pinto et al, 2011). In addition, TNP-and (M)ANTnucleotides are very potent sGC inhibitors (Gille et al, 2004;Suryanarayana et al, 2009a;Dove et al, 2014). The potent sGC inhibition by (M)ANT-nucleotides is not surprising in light of the high conservation of the catalytic domains of these enzymes (Sunahara et al, 1998;Dove et al, 2014).…”

“…Given the beneficial clinical effects of allosteric sGC activators and sGC stimulators (Stasch et al, 2011(Stasch et al, , 2015, sGC inhibition would be clearly an off-target effect of mAC inhibitors (Dove et al, 2014). However, there is evidence for pharmacological distinction between mACs and sGC with (M)ANT-and TNP-nucleotides (Dove et al, 2014) (Table 6). …”

“…In addition, TNP-and (M)ANTnucleotides are very potent sGC inhibitors (Gille et al, 2004;Suryanarayana et al, 2009a;Dove et al, 2014). The potent sGC inhibition by (M)ANT-nucleotides is not surprising in light of the high conservation of the catalytic domains of these enzymes (Sunahara et al, 1998;Dove et al, 2014). Given the beneficial clinical effects of allosteric sGC activators and sGC stimulators (Stasch et al, 2011(Stasch et al, , 2015, sGC inhibition would be clearly an off-target effect of mAC inhibitors (Dove et al, 2014).…”

“…Compounds 1 , 3, 7, 10, 11, and 20 were studied at partially purified sAC from rat testis; compounds 22-25 were studied at the purified catalytic domain of human sAC. The Table has been modified from Table 1 in Dove et al (2014). Data for mACs 1, 2, and 5 and 5C1:2C2 were taken from the literature as noted by the footnotes.…”