Medicinal Chemistry of Drugs Acting on Central and Peripheral Opioid Receptors

National Institute On Drug Abuse

Investigators

Linked publications, trials & patents

Abstract

The U.S. opioid overdose deaths in 2024 have declined 36% to 48,422 from 2023, however, they still exceed the deaths from firearms, motor vehicle accidents, suicides and homicides combined (46,728). The U.S. availability of fentanyl (50x morphine), its analogs and ultra-potent congeners (up to 6000x morphine) is continuing to spread across the U.S as criminal group producers in Mexico and China continue to supply vast quantities of these drugs. This is largely due to ease of manufacturing, high potency, and low cost of the synthetic opioids compared to the much more labor intensive and costly production of heroin from cultivation and processing of opium poppies. Recently, the nitazenes have increasingly appeared on the illicit world market. These compounds exemplified by etonitazene (1000x morphine) were until recently a largely obscure group of benzimidazoles. Fortunately, like fentanyl, their opioid effects are reversible by naloxone. Overall, the present situation has been greatly exacerbated by the appearance of the nitazenes, designer analogs, counterfeit pharmaceuticals, unknown drug mixtures and counterfeit tablets with heterogenous mixtures of fentanyl and etonitazene in inert material. The recent appearance of brightly colored fentanyl tablets designed to resemble children’s candy- Sweet Tarts -is a particularly outrageous example. We are continuing to pursue four approaches to combat the opioid epidemic. (1) Anti-opioid vaccines against (a) heroin, (b) fentanyl and (c) a combination vaccine against mixtures of heroin and fentanyl. These vaccines each produce high-titer, high-affinity antibodies against the target drug(s) that blunted the in vivo effects in rats and mice, and critically, did not recognize any of the treatment drugs: methadone, naloxone, naltrexone or buprenorphine. Our anti-heroin vaccine prevented heroin-induced antinociception following repeated IV heroin challenges for over a year in immunized rats. Our IND for the anti-heroin vaccine submitted to the FDA earlier has now been approved and we will soon begin clinical studies. Licensing of our combination anti-heroin and anti-fentanyl vaccine, and our anti-fentanyl monoclonal antibody patent technology is presently in progress. We initially used tetanus toxoid as the immunogenic protein-like carrier molecule for our novel vaccines against heroin and fentanyl, however, tetanus toxoid is not ideal because of the cost and toxicity. We have now found that bacterial protein mutant Q-beta (mQ can serve a carrier for the antigen. It is a powerful immunogenic carrier of the small molecule hapten 6-AmHap mimicking heroin. The mQβ-6-AmHap conjugate was able to induce significantly higher levels of IgG antibodies against 6-AmHap than mice immunized with the corresponding tetanus toxoid-6-AmHap conjugate in head-to-head comparison studies in multiple strains of mice. The IgG antibody responses were persistent with high anti-6-AmHap titers 600 days after being immunized with mQβ-6-AmHap. We are also investigating (2) the design and chemical synthesis of improved opioid antagonists with higher antagonist potency and selectivity for MOR to combat the ultrapotent synthetics such as the nitazenes. In the 5-phenylmorphan series, we have identified several new MOR receptor antagonists that are as much as 50x as potent as naltrexone in the in vitro cAMP assay and unlike naltrexone do not show MOR agonist activity. We are also developing (3) partial MOR agonists with reduced respiratory depression and GI effects as novel and safer medications to treat pain and OUD. These compounds may serve as replacements for classical narcotics presently used in clinical medicine. Lastly, (4) we are developing a highly selective [18F]-labeled MOR ligand, fluonitrazine (FNZ), as a novel, improved imaging agent for positron emission tomography (PET) to replace/compliment [11C]carfentanyl. Our preliminary studies show that tritiated FNZ exhibits a very robust MOR pattern in rat brain autoradiograms.