Medicinal Chemistry of Drugs Acting on Central and Peripheral Opioid Receptors

National Institute On Drug Abuse

Investigators

Linked publications & trials

Abstract

The abuse of opioids continues at epidemic levels with devastating consequences in the past year. Deaths from opioid overdose have continued to increase and now exceed those from firearms, motor vehicle crashes, suicides and homicides. In 2020, more than 68,800 Americans died from opioid overdose. The U.S. availability of fentanyl, its analogs and ultra-potent congeners has continued to increase and spread across the U.S as criminal group producers in Mexico and China continue to drive the supply of these drugs. The abuse of fentanyl and designer analogs is rapidly escalating and the most recent data indicate that these drugs were responsible for more than 55,000 overdose fatalities annually exceeding those where heroin was the causative agent. 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 containing fentanyl and derivatives such as ultra-potent carfentanyl in lethal doses. Anti-Opioid Vaccines as Countermeasures to the Opioid Epidemic: We have made substantial progress in each of the three approaches that we are currently pursuing to dealing with the opioid epidemic. The first is the ultimate development of a combination trivalent (or separate) anti-heroin, anti-HIV, antifentanyl vaccine(s). A successful combination vaccine of this type would suppress heroin and fentanyl abuse and protect against HIV infection from any route of exposure. Since injection drug use is a major factor in the transmission of HIV-1, suppression of the accompanying needle sharing would limit the spread of HIV and hepatitis in injection drug users. Such a vaccine should also be a valuable adjunct to prevent relapse in newly abstinent former narcotic abusers. This is an important consideration as the relapse rate for those able to quit is as high as 60% in the first year. We are continuing to prepare and evaluate experimental vaccines based on our novel approach of utilization of metabolically stable heroin-mimetic haptens. These haptens were covalently attached to the highly immunogenic tetanus toxoid (TT) with or without an HIV component and formulated with the Army Liposome Formulation. In collaboration with researchers at the Walter Reed Army Institute of Research, one such vaccine was derived from our lead heroin hapten 6-Amhap. The TT-6-AmHap vaccine significantly reduced heroin-induced antinociception and locomotion behavioral changes. We also examined the efficacy of the TT-6-AmHap vaccine in mice in the locomotion assay after a high-dose heroin challenge. We administered heroin at 50 mg/kg SC and found partial protection even at this dose of 50 times the ED50. Competition ELISA demonstrated that 6-AmHap-induced antibodies bound heroin and its metabolites, 6-acetylmorphine, morphine, and other abused opioids, including oxycodone, hydrocodone and hydromorphone. The antibodies did not cross-react with the therapies for substance abuse or the overdose rescue drug naloxone. The HIV portion of one of our vaccines related to TT-6-AmHap utilized a cyclic V2 (cV2) peptide previously identified as a correlate of prevention of acquisition of HIV in the RV144 phase III clinical trial. RV144 is the only HIV vaccine trial that has demonstrated such efficacy to date. We immunized mice and sera were assessed for antibody titer to heroin and cV2. We assessed efficacy against heroin by subcutaneous heroin challenge. Antibody titers to cV2 were in the millions and bound to gp120 and gp70V1V2. The heroin-HIV vaccine induced protection against heroin challenge and afforded a very high titer cV2 antibodies, a proposed a correlate of efficacy in RV144. We conclude that an effective heroin-HIV vaccine is feasible based on our data. Our 6-AmHap anti-heroin vaccine is on track to enter phase 1 clinical trials at SUNY Upstate Medical School as soon as we receive FDA approval. We have also made substantial progress in the development of our anti-fentanyl vaccine. In mice, immunization induced high and robust antibody endpoint titers in the order of millions against the hapten. The antisera bound fentanyl, carfentanil, cyclopropyl fentanyl, para-fluorofentanyl, and 2-furanyl fentanyl in vitro with antibody-drug dissociation constants in the range of 0.36 4.66 nM. The antisera did not show cross-reactivity to naloxone, naltrexone, methadone, or buprenorphine. In vivo, the antinociceptive dose-response curve of fentanyl was right shifted to higher doses after immunization. Our preclinical results collectively showed the desired traits of a potential vaccine against fentanyl and demonstrated the feasibility of immunization to combat fentanyl-induced effects. We and our collaborators have also begun a study using chimeric monoclonal antibodies (mAb) that block fentanyl effects and alter fentanyl biodistribution in mice. This study is the first report of chimeric mAb against fentanyl and its analogs. We have engineered and identified, through in vitro characterization and in vivo animal challenge studies, two mAb candidates with very high (0.1-1.3 nM) binding affinities to fentanyl and its analogs and are effective in engaging fentanyl in the periphery and blocking its effects in challenged animals. G-protein Biased Agonists: Our second approach is the development of G-protein biased agonists as potential analgesics that lack the undesirable side effects of morphine (including respiratory depression, constipation and the development of tolerance and dependence). These drugs would replace the narcotic analgesics presently in use in the practice of medicine. We have identified three novel compounds in the 5-phenylmorphan series that act as morphine-like mu receptor agonists (3, 4 and 5 times more potent than morphine) in vitro but do not recruit the beta-arrestin pathway at all in two independent assays. The beta-arrestin pathway has been thought to mediate the undesirable side effects (addiction, tolerance, respiratory depression and constipation) of narcotic drugs. Recent literature suggests that partial MOR agonists, compounds with moderate or low efficacy, may reduce or eliminate the unfortunate opioid side-effects that render the use of current analgesics problematic. One of these compounds does not appear to cause respiratory depression, the major factor in overdose deaths, in squirrel monkeys under adverse conditions of hypercapnia. Several others are being investigated at this time. These compounds will be explored for their gastrointestinal effects and their ability to induce tolerance in the near future. We have also begun collaboration with NIDA Intramural quantum chemists for molecular mechanics investigation of these MOR partial agonists. Also, we carried out studies to further characterize the effects of methylone, 3,4-methylenedioxypyrovalerone, and alpha-ethylphenethylamine homologs of amphetamine. The latter are unregulated dietary supplements and components of energy rub lotions. We found that these compounds act on biogenic amine receptors similar to amphetamine and may pose risks to humans because of cardiovascular effects and abuse potential. MOR-DOR Opioid Receptor Agonists: The third approach in our triad is the design and chemical synthesis of combination MOR-DOR-opioid receptor agonists. We have identified one such drug that was a potent mu receptor partial agonist about 50 x morphine and does not show the respiratory depression produced by morphine in normal air in a rodent and primate assay. Prior drug combination studies by others have shown that such MOR-DOR compounds may lack the potentially fatal respiratory depression shown by morphine, fentanyl and congeners.