Jacobson, Kenneth (NIDDK)
Tosh, Dilip (NIDDK)
Reitman, Marc (NIDDK)
Gavrilova, Oksana (NIDDK)
This technology includes a compound for use as a selective agonist of the A1 adenosine receptor (AR) for therapeutic hypothermia and other conditions. We have examined various synthesized nucleosides in a model of mouse hypothermia, in conjunction with AR knockout mice, to characterize the biological profiles. In trying to identify novel highly selective A1AR agonists that have superior in vivo activities, we have adapted a means of rigidifying the ribose moiety of adenosine in the form of a bicyclic (N)-methanocarba ring. We identified and modeled the N6-bicyclobutylmethyl group as a new substituent for the design of A1AR agonists, and peripherally administered compound 9 (MRS7469, containing this group) predominantly activates A1AR in the brain to lower body temperature. In the parallel methanocarba series, enhancement of A1AR affinity and selectivity was found with an alternative nucleobase, which opens the field for more broad synthesis of atypical A1AR agonists.
These compounds could potentially be used for therapeutic hypothermia (i.e., to protect the brain in cases of cardiac arrest or stroke). There is also potential for their use in chronic pain, diabetes, cardiac arrhythmias, myocardial infarction, depression and brain ischemia.
Compound is bioavailable and drug-like, with no evident toxicity or potent off-target effects.