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. These PAMs potentiate dopamine-stimulated G-protein and 13-arrestin-mediated signaling of the D1R. Several analogs of the D1R PAM compounds have been synthesized and characterized.
PAMs should have an increased selectivity for the D1 dopamine receptor while minimizing off-target side effects.
The PAMs may have several advantages over existing synthetic orthosteric agonists, which bind to the same site as dopamine. PAMs potentiate the receptor activation caused by dopamine, but there is a limit to the potentiation caused by the PAM. This can result in a larger therapeutic window, compared to a synthetic orthosteric agonist, which can overstimulate the receptor resulting in adverse side effects. Also, by their nature, PAMs bind to a site on the receptor that is different from the dopamine binding site that is targeted by orthosteric ligands.