Truncated Nucleosides As A(3) Adenosine Receptor Ligands: Combined 2-Arylethynyl and Bicyclohexane Substitutions

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2012 Nov 13

PMID 23145215

Citations 16

Authors

Dilip K Tosh

Silvia Paoletta

Khai Phan

Zhan-Guo Gao

Kenneth A Jacobson

Affiliations

Soon will be listed here.

Abstract

C2-Arylethynyladenosine-5'-N-methyluronamides containing a bicyclo[3.1.0]hexane ((N)-methanocarba) ring are selective A(3) adenosine receptor (AR) agonists. Similar 4'-truncated C2-arylethynyl-(N)-methanocarba nucleosides containing alkyl or alkylaryl groups at the N(6) position were low-efficacy agonists or antagonists of the human A(3)AR with high selectivity. Higher hA(3)AR affinity was associated with N(6)-methyl and ethyl (K(i) 3-6 nM), than with N(6)-arylalkyl groups. However, combined C2-phenylethynyl and N(6)-2-phenylethyl substitutions in selective antagonist 15 provided a K(i) of 20 nM. Differences between 4'-truncated and nontruncated analogues of extended C2-p-biphenylethynyl substitution suggested a ligand reorientation in AR binding, dominated by bulky N(6) groups in analogues lacking a stabilizing 5'-uronamide moiety. Thus, 4'-truncation of C2-arylethynyl-(N)-methanocarba adenosine derivatives is compatible with general preservation of A(3)AR selectivity, especially with small N(6) groups, but reduced efficacy in A(3)AR-induced inhibition of adenylate cyclase.

Citing Articles

Covalently Binding Adenosine A Receptor Agonist ICBM Irreversibly Reduces Voltage-Gated Ca Currents in Dorsal Root Ganglion Neurons.

Cherchi F, Venturini M, Magni G, Scortichini M, Jacobson K, Pugliese A Purinergic Signal. 2023; 20(1):35-45.

PMID: 36918461 PMC: 10828244. DOI: 10.1007/s11302-023-09929-y.

Therapeutic Potential of Highly Selective A Adenosine Receptor Ligands in the Central and Peripheral Nervous System.

Coppi E, Cherchi F, Venturini M, Lucarini E, Corradetti R, Di Cesare Mannelli L Molecules. 2022; 27(6).

PMID: 35335254 PMC: 8952202. DOI: 10.3390/molecules27061890.

Interaction of A adenosine receptor ligands with the human multidrug transporter ABCG2.

Abel B, Murakami M, Tosh D, Yu J, Lusvarghi S, Campbell R Eur J Med Chem. 2022; 231:114103.

PMID: 35152062 PMC: 8893036. DOI: 10.1016/j.ejmech.2022.114103.

Truncated (N)-Methanocarba Nucleosides as Partial Agonists at Mouse and Human A Adenosine Receptors: Affinity Enhancement by -(2-Phenylethyl) Substitution.

Tosh D, Salmaso V, Rao H, Bitant A, Fisher C, Lieberman D J Med Chem. 2020; 63(8):4334-4348.

PMID: 32271569 PMC: 7443318. DOI: 10.1021/acs.jmedchem.0c00235.

Evidence for the Interaction of A Adenosine Receptor Agonists at the Drug-Binding Site(s) of Human P-glycoprotein (ABCB1).

Abel B, Tosh D, Durell S, Murakami M, Vahedi S, Jacobson K Mol Pharmacol. 2019; 96(2):180-192.

PMID: 31127007 PMC: 6608608. DOI: 10.1124/mol.118.115295.

References

Tosh D, Chinn M, Ivanov A, Klutz A, Gao Z, Jacobson K . Functionalized congeners of A3 adenosine receptor-selective nucleosides containing a bicyclo[3.1.0]hexane ring system. J Med Chem. 2009; 52(23):7580-92. PMC: 3109436. DOI: 10.1021/jm900426g. View

Hou X, Majik M, Kim K, Pyee Y, Lee Y, Alexander V . Structure-activity relationships of truncated C2- or C8-substituted adenosine derivatives as dual acting A₂A and A₃ adenosine receptor ligands. J Med Chem. 2011; 55(1):342-56. PMC: 3266722. DOI: 10.1021/jm201229j. View

Jacobson K, Ji X, Li A, Melman N, Siddiqui M, Shin K . Methanocarba analogues of purine nucleosides as potent and selective adenosine receptor agonists. J Med Chem. 2000; 43(11):2196-203. PMC: 3471159. DOI: 10.1021/jm9905965. View

Gessi S, Merighi S, Varani K, Cattabriga E, Benini A, Mirandola P . Adenosine receptors in colon carcinoma tissues and colon tumoral cell lines: focus on the A(3) adenosine subtype. J Cell Physiol. 2007; 211(3):826-36. DOI: 10.1002/jcp.20994. View

Tchilibon S, Joshi B, Kim S, Duong H, Gao Z, Jacobson K . (N)-methanocarba 2,N6-disubstituted adenine nucleosides as highly potent and selective A3 adenosine receptor agonists. J Med Chem. 2005; 48(6):1745-58. PMC: 3463111. DOI: 10.1021/jm049580r. View

Auchampach J, Gizewski E, Wan T, de Castro S, Brown Jr G, Jacobson K . Synthesis and pharmacological characterization of [(125)I]MRS5127, a high affinity, selective agonist radioligand for the A3 adenosine receptor. Biochem Pharmacol. 2009; 79(7):967-73. PMC: 2815200. DOI: 10.1016/j.bcp.2009.11.009. View

Gessi S, Merighi S, Sacchetto V, Simioni C, Borea P . Adenosine receptors and cancer. Biochim Biophys Acta. 2010; 1808(5):1400-12. DOI: 10.1016/j.bbamem.2010.09.020. View

Ohsawa K, Sanagi T, Nakamura Y, Suzuki E, Inoue K, Kohsaka S . Adenosine A3 receptor is involved in ADP-induced microglial process extension and migration. J Neurochem. 2012; 121(2):217-27. DOI: 10.1111/j.1471-4159.2012.07693.x. View

Chen Z, Janes K, Chen C, Doyle T, Bryant L, Tosh D . Controlling murine and rat chronic pain through A3 adenosine receptor activation. FASEB J. 2012; 26(5):1855-65. PMC: 3336784. DOI: 10.1096/fj.11-201541. View

10.

Volpini R, Buccioni M, Dal Ben D, Lambertucci C, Lammi C, Marucci G . Synthesis and biological evaluation of 2-alkynyl-N6-methyl-5'-N-methylcarboxamidoadenosine derivatives as potent and highly selective agonists for the human adenosine A3 receptor. J Med Chem. 2009; 52(23):7897-900. DOI: 10.1021/jm900754g. View

11.

Bar-Yehuda S, Luger D, Ochaion A, Cohen S, Patokaa R, Zozulya G . Inhibition of experimental auto-immune uveitis by the A3 adenosine receptor agonist CF101. Int J Mol Med. 2011; 28(5):727-31. PMC: 3167223. DOI: 10.3892/ijmm.2011.753. View

12.

Nordstedt C, Fredholm B . A modification of a protein-binding method for rapid quantification of cAMP in cell-culture supernatants and body fluid. Anal Biochem. 1990; 189(2):231-4. DOI: 10.1016/0003-2697(90)90113-n. View

13.

Jacobson K, Siddiqi S, Olah M, Ji X, Melman N, Bellamkonda K . Structure-activity relationships of 9-alkyladenine and ribose-modified adenosine derivatives at rat A3 adenosine receptors. J Med Chem. 1995; 38(10):1720-35. PMC: 3445626. DOI: 10.1021/jm00010a017. View

14.

Jeong L, Pal S, Choe S, Choi W, Jacobson K, Gao Z . Structure-activity relationships of truncated D- and l-4'-thioadenosine derivatives as species-independent A3 adenosine receptor antagonists. J Med Chem. 2008; 51(20):6609-13. PMC: 3616494. DOI: 10.1021/jm8008647. View

15.

Gao Z, Verzijl D, Zweemer A, Ye K, Goblyos A, IJzerman A . Functionally biased modulation of A(3) adenosine receptor agonist efficacy and potency by imidazoquinolinamine allosteric enhancers. Biochem Pharmacol. 2011; 82(6):658-68. PMC: 3152598. DOI: 10.1016/j.bcp.2011.06.017. View

16.

Fishman P, Bar-Yehuda S, Liang B, Jacobson K . Pharmacological and therapeutic effects of A3 adenosine receptor agonists. Drug Discov Today. 2011; 17(7-8):359-66. PMC: 3289754. DOI: 10.1016/j.drudis.2011.10.007. View

17.

Tosh D, Deflorian F, Phan K, Gao Z, Wan T, Gizewski E . Structure-guided design of A(3) adenosine receptor-selective nucleosides: combination of 2-arylethynyl and bicyclo[3.1.0]hexane substitutions. J Med Chem. 2012; 55(10):4847-60. PMC: 3371665. DOI: 10.1021/jm300396n. View

18.

Cheong S, Federico S, Venkatesan G, Mandel A, Shao Y, Moro S . The A3 adenosine receptor as multifaceted therapeutic target: pharmacology, medicinal chemistry, and in silico approaches. Med Res Rev. 2011; 33(2):235-335. DOI: 10.1002/med.20254. View

19.

Bulger E, Tower C, Warner K, Garland T, Cuschieri J, Rizoli S . Increased neutrophil adenosine a3 receptor expression is associated with hemorrhagic shock and injury severity in trauma patients. Shock. 2011; 36(5):435-9. PMC: 3204900. DOI: 10.1097/SHK.0b013e318231ee2e. View

20.

Avila M, Stone R, Civan M . Knockout of A3 adenosine receptors reduces mouse intraocular pressure. Invest Ophthalmol Vis Sci. 2002; 43(9):3021-6. View