The opioid and benzodiazepine epidemic is on the rise resulting in an average of 115 deaths daily and over 11,000 deaths in 2017 due to prescription drug overdoses in the United States, according to the CDC. Clearly, alternative treatments are needed and the search for new ligands (potential new drugs) that selectively interact with specific subtypes of GABAA receptors (GABAARs) is required. The problem with current neurological drugs on the market is that they lack functional selectivity, meaning that in addition to the desired receptor or receptor subtype of interest, these drugs also target undesired receptors causing serious side effects. For example, the commonly prescribed benzodiazepine, Xanax is used to treat anxiety and panic disorders but also causes side effects such as sedation, ataxia, and amnesia, as well as euphoria, which can lead to addiction. Xanax interacts with four of the major GABAAR subtypes (α1, α2, α3 and α5) and therefore is not considered functionally selective. Since α5- or α6-containing GABAARs are not associated with the typical benzodiazepine-type side effects, utilization of novel ligands that are functionally selective for α5- or α6-containing GABAARs could provide a key to combat this epidemic. The α6-GABAAR subtype selective pyrazoloquinolinone, DK-I-56-1 has shown promise in treating migraine, trigeminal pain and schizophrenia. Deuteration of certain pyrazoloquinolinones originally synthesized in 1995 by our group revived these ligands as drug candidates by increasing their metabolic stability via utilization of the kinetic isotope effect (KIE) and thereby doubling the concentration that reaches the brain. More recently, the key lead DK-I-56-1 has been shown to be active against tic disorders such as Tourette’s syndrome. In a different area, the lead imidazodiazepine, GL-II-73 was designed as an α5-GABAAR subtype selective ligand and exhibits promise in the area of treating memory loss and depression. By design, these α5-targeting imidazodiazepines and α6-targeting pyrazoloquinolinones are functionally selective positive allosteric modulators (PAMS) for the GABAAR subtype of interest. Thus, these ligands are devoid of the sedative, amnesic, euphoric, and ataxic side effects associated with current GABAergic drugs on the market today. Therefore, these novel and safer drugs provide a potential alternative treatment for GABAAR-related neurological diseases and solution for ending the opioid and benzodiazepine epidemic.

Combatting the opioid and benzodiazepine epidemic by the synthesis of novel safer drugs designed to be functionally selective for α5- or α6-containing GABAA receptors

2019 Fall National Meeting

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