Potent adenosine hA2A receptor antagonists are often accompanied by poor aqueous solubility, which presents issues for drug development. Herein we describe the early exploration of the structure-activity relationships of a lead pyrimidin-4-yl acetamide series to provide potent and selective 2-amino-N-pyrimidin-4-yl acetamides as hA2A receptor antagonists with excellent aqueous solubility. In addition, this series of compounds has demonstrated good bioavailability and in vivo efficacy in a rodent model of Parkinson's disease, despite having reduced potency for the rat A2A receptor versus the human A2A receptor.

Transection of the chorda tympani nerve (CTX) impairs taste-guided discrimination of NaCl from KCl in rats. We wanted to determine whether this discrimination recovers after chorda tympani regeneration. Experiment 1 showed that few taste buds regenerated 14 days after CTX, whereas substantial regeneration occurred 42 days after surgery. Experiment 2 demonstrated that rats trained before CTX could clearly discriminate the two salts when tested starting 49 days after surgery, whereas rats tested starting 8 days after surgery were severely impaired in this task. Rats tested starting 28 days after CTX were unimpaired, moderately impaired, or severely impaired on the discrimination task. Overall, discrimination performance was significantly related to the number of regenerated taste buds. Unilaterally transected rats tested shortly after surgery were nearly as competent as controls. These results indicate that rats can recover the ability to discriminate NaCl from KCl after regeneration of anterior tongue taste buds.

No abstract

Cachexia is metabolic disorder characterized by anorexia, an increased metabolic rate, and loss of lean body mass. It is a relatively common disorder, and is a pathological feature of diseases such as cancer, HIV infection, and renal failure. Recent studies have demonstrated that cachexia brought about by a variety of illnesses can be attenuated or reversed by blocking activation of the melanocortin 4 subtype receptor (MC4-R) within the central nervous system. Although the potential use of central MC4-R antagonists for the treatment of cachexia was supported by these studies, utility was limited by the need to deliver these agents intracerebroventricularly. In the current study, we present a series of experiments demonstrating that peripheral administration of a small molecule MC4-R antagonist can effectively stimulate daytime (satiated) food intake as well as decrease basal metabolic rate in normal animals. Furthermore, this compound attenuated cachexia and preserved lean body mass in a murine cancer model. These data clearly demonstrate the potential of small molecule MC4-R antagonists in the treatment of cachexia and underscore the importance of melanocortin signaling in the development of this metabolic disorder.