Medicinal Chemistry of Drugs Acting on Central and Peripheral Opioid Receptors

National Institute On Drug Abuse

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Abstract

The opioid overdose epidemic has continued to worsen during the reporting period with devastating consequences in the U.S. Recent data from the CDC shows that nearly 288,000 Americans died during 1999-2021 from overdose involving synthetic drugs (other than methadone), principally fentanyl and congeners that are now the major problem. Mexican criminal cartel producers continue to supply vast quantities of these synthetic drugs using precursor chemicals sourced from China. This entire situation is exacerbated by the availability of fentanyl-heroin mixtures, counterfeit drugs of different types containing varying amounts of fentanyl, and derivatives such as ultra-potent carfentanyl in lethal doses. In addition, the extremely potent etonitazene and related benzimidazoles (nitazenes) have become a growing problem. The recent appearance of xylazine, a veterinary tranquilizer in these drug mixtures has further complicated the overall situation. The following example will serve to illustrate the magnitude of the epidemic. In 2022, DEA seized more than 58 million fentanyl-containing pills and more than 13,000 pounds of fentanyl powder. The 2022 seizures are equivalent to more than 387.9 million lethal doses of fentanyl, more than enough to fatally dose the entire U.S. population. Deaths from opioid overdose now exceed those from firearms, motor vehicle crashes, suicides, or homicides. We have extended our program to develop countermeasures to the opioid abuse to include vaccines against fentanyl and closely related analogs, and heroin and its active metabolites 6-acetylmorphine and morphine. Our anti-fentanyl vaccine produces a high antibody titer of greater than a million that binds fentanyl, and five analogs including the ultrapotent carfentanyl. These antibodies do not bind any of the treatment medications including methadone, naloxone, naltrexone and buprenorphine. In the tail immersion test for analgesia with mice immunized with our anti-fentanyl vaccine, the dose response curve was shifted 4.3-fold to the right. In the hot plate assay, the dose response curve was shifted 8-fold to the right. We also developed two novel monoclonal antibodies to fentanyl. Monoclonal antibodies P1C3H9 and P1B6H7 bound fentanyl with 0.15, and 1.28 nM affinity, respectively. Administration of these antibodies to mice followed by fentanyl nearly eliminated the action of fentanyl in the tail immersion assay. These antibodies did not bind the four treatment drugs above. We have also constructed a combination vaccine to induce dual immune response to fentanyl, and heroin and its active metabolites. Mixing 10 micrograms each of our 6-Amhap-tetanus toxoid and p-AmFenhap -tetanus toxoid conjugates followed by immunization of mice yielded antisera that bound fentanyl and heroin and its metabolites above with sub-nM affinity. This antisera did not bind any of the treatment medications above. Our bivalent vaccine right-shifted the dose response curves in immunized mice for heroin, fentanyl and a 1:10 fentanyl-heroin mixture by 3.5, 6.7 and 3.4, respectively. We designed and synthesized four sets of chiral C-9-alkenyl 5-phenylmorphans using the enantiomeric 9-keto intermediates we previously described from our optimized synthesis. The resulting compounds of known absolute stereochemistry were studied in several assays to provide further insight into relation of stereochemistry and pharmacological profile in this series. We found three MOR antagonists that were equipotent or more potent than naltrexone but without any agonist activity at DOR or KOR, unlike naltrexone. Importantly, MOR partial agonists with less respiratory depression than morphine were found along with potent MOR agonists. These studies provide excellent examples of the influence of stereochemistry on biological activity in this series. Earlier, we synthesized the ghrelin receptor antagonist PF-6870961 through a difficult 13-step synthesis that involved instable chemical intermediates. We have now completed our resynthesis of PF-6870961 and obtained 5.0 grams of this material as a pure crystalline solid. Our studies showed PF-6870961is an inverse agonist at the ghrelin receptor and that it suppressed food intake in male and female rats. In addition, PF-6870961 also suppressed alcohol intake in male and female mice suggesting its utility in the treatment of alcohol use disorder.