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This technology relates to the creation and use of newly identified ligands to the D1 dopamine receptor (D1R). The D1 dopamine receptor is linked to a variety of neuropsychiatric disorders and represents an attractive drug target for the enhancement of cognition in schizophrenia, Alzheimer disease, and other disorders. These ligands are positive allosteric modulators (PAMs) that bind to the dopamine receptor at a site other than where dopamine binds and causes the receptor to have an increased response.

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.

This technology includes A1AR-selective agonists which are full or partial agonists of the A1AR and are being considered for treatment of various conditions: seizures, stroke, diabetes, pain, cardio-protection and arrhythmias. A1AR agonists are highly neuroprotective in ischemic and epileptic models. A1AR agonists are also being explored for antidepressant, antianxiety, and other neuropsychiatric effects, due to their presynaptic action to decrease the release of excitatory amino acids in the brain.

This technology includes a cell line to be used for the study of anti-psychotic therapies and potentially Parkinson’s disease. Activation of D1 dopamine receptors plays a critical role in many fundamental CNS processes. M4 mAChRs are coexpressed with D1 dopamine receptors in a specific subset of striatal medium spiny neurons that contain GABA as the major neurotransmitter. The present study used Cre/LoxP technology to generate mutant mice that lack M4-¬-AChRs only in D1 dopamine receptor-¬-expressing cells to investigate the physiological relevance of mAChRs in this neuronal subpopulation.