RT Journal Article
SR Electronic
T1 Structure-activity relationships of the sustained effects of adenosine A2A receptor agonists driven by slow dissociation kinetics
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.116.105551
DO 10.1124/mol.116.105551
A1 J. Daniel Hothersall
A1 Dong Guo
A1 Sunil Sarda
A1 Robert J Sheppard
A1 Hongming Chen
A1 Wesley Keur
A1 Michael J Waring
A1 Adriaan P. IJzerman
A1 Stephen J Hill
A1 Ian L Dale
A1 Philip Rawlins
YR 2016
UL http://molpharm.aspetjournals.org/content/early/2016/10/28/mol.116.105551.abstract
AB The duration of action of adenosine A2A receptor (A2A) agonists is critical for their clinical efficacy, and we sought to better understand how this can be optimized. The in vitro temporal response profiles of a panel of A2A agonists were studied using cAMP assays in recombinantly (CHO) and endogenously (SH-SY5Y) expressing cells. Some agonists (e.g. 3cd; UK-432,097) but not others (e.g. 3ac; CGS-21680) demonstrated sustained wash-resistant agonism, where residual receptor activation continued after washout. The ability of an antagonist to reverse pre-established agonist responses was used as a surrogate read-out for agonist dissociation kinetics, and together with radioligand binding studies suggested a role for slow off-rate in driving sustained effects. One compound, 3ch, showed particularly marked sustained effects, with a reversal t½ > 6 hours and close to maximal effects that remained for at least 5 hours after washing. Based on the SAR of these compounds, we suggest that lipophilic N6 and bulky C2 substituents can promote stable and long-lived binding events leading to sustained agonist responses, although a high compound logD is not necessary. This provides new insight into the binding interactions of these ligands and we anticipate that this information could facilitate the rational design of novel long-acting A2A agonists with improved clinical efficacy.