Description
NKY-80 (299442-43-6) is a potent and selective adenylyl cyclase inhibitor. Selective for AC5 and over AC3 and AC2 (IC50 = 8.3 μM, 132 μM and 1.7 mM respectively).1,2 More recently shown to indiscriminately inhibit AC6.3 NKY-80 is an extremely useful tool for probing the involvement of adenylyl cyclases in cellular signaling.4
Uses
NKY 80 is an inhibitor of adenylyl cyclase (AC) and displays a greater affinity for AC5 over AC3 and AC2. Adenyl cyclase inhibitors can be easily modified by tumor targeting structures.
General Description
A cell-permeable quinazolinone containing a non-nucleoside compound that acts as a potent, selective inhibitor of adenylyl cyclase (AC) type V isoform (IC
50 = 8.3 μM, 132 μM and 1.7 mM for type V, III and II, respectively) in the presence of G
sα GTPγS-Forskolin. Displays ~210-fold greater selectivity for type V over the type II isoform. The inhibition is non-competitive with respect to ATP and Forskolin. Regulates the AC catalytic activity in heart and lung tissues.
Biochem/physiol Actions
Cell permeable: yes
Background
NKY-80 is an inhibitor of adenylyl cyclase catalytic activity, an essential enzyme that generates cyclic adenosine 3'5'-monophosphate from ATP. At least six distinct classes of ACs have been identified, with isozymes differing in cell localization, tissue distribution, and signaling pathways. NKY-80 is capable of blocking several different AC isozymes, inhibiting type V more strongly than type II or type III. NKY-80 also potently inhibits AC type VI, with an affinity close to that of AC type V. In a rat model of Parkinson's disease, NKY-80 blocked increases of both [(3)H]-GABA release and cAMP production, indicating that AC V/VI expression is a major determinant of increased GABAergic transmission in rats with L-DOPA induced severe dyskinesia. In a study of immune response in insects, NKY-80 reduced levels of hemocyte mobilization in response to bacterial challenge, indicating a role for AC and cAMP in hemocyte regulation and the immune response.
References
[1] Type-specific regulation of adenylyl cyclase. Selective pharmacological stimulation and inhibition of adenylyl cyclase isoforms
[2] SANDRA PIERRE. Capturing adenylyl cyclases as potential drug targets[J]. Nature Reviews. Drug Discovery, 2009, 8 4: 321-335. DOI:
10.1038/nrd2827[3] CAMERON S BRAND. Isoform selectivity of adenylyl cyclase inhibitors: characterization of known and novel compounds.[J]. Journal of Pharmacology and Experimental Therapeutics, 2013, 347 2: 265-275. DOI:
10.1124/jpet.113.208157[4] M CECILIA ORTIZ-CAPISANO. Adenylyl cyclase isoform v mediates renin release from juxtaglomerular cells.[J]. Hypertension, 2007, 49 3: 618-624. DOI:
10.1161/01.hyp.0000255172.84842.d2
