Medicinal Chemistry of Drugs Acting on Central and Peripheral Opioid Receptors

National Institute On Drug Abuse

Investigators

Linked publications, trials & patents

Abstract

Opioid abuse continues at epidemic levels with devastating consequences in the U.S. in the past year. Recent data from the CDC show that deaths from opioids increased to 75,673 in the 12-month period ending in April 2021, up 35% from 56,064 in just one year. Overdose deaths from synthetic opioids other than methadone (primarily fentanyl and its congeners) are largely driving this increase as criminal group producers in Mexico and China continue to supply vast quantities of these drugs. Recently, the extremely potent etonitazene and related benzimidazoles have become a growing problem. This entire situation is exacerbated by the availability of heroin-fentanyl mixtures, counterfeit drugs of different types containing varying amounts of fentanyl and derivatives such as ultra-potent carfentanyl in lethal doses. Deaths from opioid overdose now exceed those from firearms, motor vehicle crashes, suicides, or homicides. We have continued to make excellent progress in our development of countermeasures to the opioid problem during the reporting period. We published our successful work on development of a C1-linked and a C14-linked hapten vaccine and on a dual anti-fentanyl-heroin vaccine. We developed high affinity chimeric monoclonal antibodies that block fentanyl effects in challenged animals. We also synthesized a major metabolite of the ghrelin receptor inverse agonist PF-5190457 that may be useful in the treatment of alcohol use disorder. This was a long and difficult synthesis that required 13 steps and involving unstable synthetic intermediates, however we obtained in excess of 2.0 grams of pure crystalline PF-6870961. We expect a resynthesis in progress to provide in excess of 5.0 grams. We also published our large-scale chemical synthesis of a 9-keto-5-phenylmorphan needed as starting material in our search for novel opioid agonist and antagonists. We optimized the route and obtained 1.2 kg of a quaternary salt as the direct precursor of the 9 keto-5-phenylmorphan. In a noteworthy advance, we eliminated the problematic batch size limitation that had been inherent in the last step of the synthesis since its disclosure in 1955. This development greatly simplifies scaleup of the synthesis of our required intermediate and renders it now readily available.