First of all, I want to acknowledge and Dr. Hoang Le thanks for his continued guidance and encouragement over the past two and a half years. I want both Dr. Thanks to Seong Jong Kim and Nick Akins for their support, patience and teachings throughout my time in the lab. Furthermore, I would like to thank Sydney Harrison for her help and continued friendship over the past two years.
I would like to thank Dr. John Rimoldi for their time and input as members of my committee, along with Dr. I would also like to thank the Sally McDonnel Barksdale Honors College for this opportunity to work with such great people, as well as providing partial funding for this research project. Finally, I would like to thank my friends and family who have given me so much support over the years. James Campbell's 1995 presidential address to the American Pain Association, where he called for patient pain to be included as a vital sign. these drugs have led to a steady increase in opioid-related drug overdoses, with 47,600 of the 70,237 drug-related deaths involving opioids in 2017.3,4 Opioid analgesics most commonly act on the mu-opioid receptor (MOR), 7,8 which is one of four G protein-coupled receptors that make up the opioid system.
Dagiti nabati a tallo ket ti kappa-opioid a reseptor (KOR), ti delta-opioid a reseptor (DOR), ken ti nociceptin-opioid a reseptor (NOR). CNS Sentral a sistema ti nerbio DOR Delta-opioid a reseptor KOR Kappa-opioid a reseptor MOR Mu-opioid a reseptor.
Introduction
- The Opioid Epidemic
- Opioid Receptors
- Biochemical & Neurological Mechanisms of Addiction
- Salvinorin A
- PR-38 and AK-1401
- Amide-Linked Compounds
Chronic pain is one of the most common conditions that involve the prescription of opioids as treatment.17 In September 2018, the CDC estimated that approximately 50 million Americans live with chronic pain, with the largest majority demographic being those aged 45-64 year. .17 In addition to the problem of many Americans living with chronic pain, approximately 43 million Americans of mental illness.18 While opioids have proven to be successful in the treatment of both illnesses, the known effects of long-term use include: hypothalamus-pituitary-adrenal dysregulation, sleep-. In humans, there are three classical opioid receptors called mu (MOR), delta (DOR) and kappa (KOR) opioid receptors, as well as a single non-classical receptor known as the nociceptin opioid receptor (NOR). 20 opioid receptors belong to a subgroup of seven transmembrane G protein-coupled receptors (GPCRs) and show between 50-70% gene homology.21 Agonists of all three classical opioid receptors often act as analgesics.21 MOR agonists have been shown to help in the treatment of addiction, tolerance, decreased intestinal motility and respiratory depression, while antagonists have been shown to treat addiction and overdose.31-34 DOR agonists have recently gained popularity in the clinical setting for their ability to treat chronic pain and control negative emotional states. ; however, high doses often lead to convulsions.35,36. Upon binding of a ligand to the opioid receptors, a conformational change occurs which enables intracellular coupling of the heterotrimeric Gi/o proteins to the carboxyl terminus of the receptor.20 The binding of GTP to the Gα subunit replaces GDP and causes a dissociation of the trimeric G protein complex into its Ga and Gbg subunits.20 The Ga subunit inhibits adenylyl cyclases and cAMP production, while the Gbg subunit interacts directly with ion channels in the membrane (Figure 6.).22,23.
All three classical opioid receptors have been shown to have the ability to modulate both pre- and postsynaptic Ca2+ channels, thereby reducing neuronal excitability and/or the release of pronociceptive neuropeptides.24 As opioid receptors are GPCRs, they are sensitive to phosphorylation by GPCR kinases.25 When when the receptor is phosphorylated, it is susceptible to binding by a class of proteins known as b-arrestins.25 After phosphorylation, b-arrestins bind to the receptor, preventing Much of the intense pleasure associated with opioids is the result. Salvinorin A is an active metabolite from the Mexican hallucinogenic sage bush Salvia divinorum (Figure 1.8).42 Salvinorin A is of great chemical interest for several reasons.
It crosses the blood-brain barrier rapidly and has a half-life of approximately 8 minutes.44 This short half-life is partly due to the rapid hydrolysis of the C-2 acetate by esterases.45,46 The intense hallucinogenic effects, as well as the rapid hydrolysis of the active metabolite, makes salvinorin a poor drug of choice for the treatment of pain and mental illness. Jordan Zjawiony of the University of Mississippi's Department of Biomolecular Sciences has used the structure of salvinorin A as a basis for the synthesis of new compounds for opioid receptors, and through his research efforts his group has discovered PR-38 and AK-1401. , two important compounds that have dual activity on KOR and MOR (Figure 1.9). Zjawiony's group hypothesized that the nitrogen on the indole is responsible for conferring affinity on the MOR by.
Similar to salvinorin A, the C-2 ester undergoes hydrolysis by esterases in the body, shortening the time the drug is bioavailable. The Hoang Le laboratory has designed and synthesized a series of ester compounds with different 6,5-rings fused at C-2 of the salvinorin scaffold. Our aim was to test the two hypotheses mentioned above regarding the structure of salvinorin.
Our goal was to determine whether the nitrogen atom in the 6.5-fused ring system would lead to the selectivity of the MOR over the KOR and to determine its effects. We also planned to use these synthetic salvinorin compounds to investigate the classical opioid receptors to determine what activity and functionality could be achieved and/or improved by chemically altering the 6,5-fused ring system. Our studies have shown that the hypothesis that an aromatic ring at C-2 was responsible for the switch to dual activity at MOR and KOR is not true, as several of our compounds that are not aromatic at C-2 still retain the dual activity at own MOR and KOR. KOR.
Furthermore, we found that the location of the nitrogen(s) and other heteroatoms within the 6.5-fused ring system play a role in binding affinity, but did not confer selectivity for MOR alone. We also want to determine whether the chemical linkers have any effect on the binding affinity and selectivity of the ligands.
Experimental Procedures
Conversion of Salvinorin B to Amino-salvinorin via
General Procedure for the Coupling of Amino-salvinorin
Results…
These compounds will give us useful insight into the role of different linkers in conferring selectivity to one or more classical opioid receptors. The purpose of using bioisosteres in linkers is to synthesize compounds with similar binding affinities that are less toxic and less susceptible to enzymatic degradation in the body, which will lead to increased bioavailability.50-51 We are also looking to use computational modeling to try and determine key interactions between the linker and/or the 6,5-fused ring system in conferring selectivity to one, two, or all three opioid receptors. This will make us better able to design the next generation of salvinorin compounds with increased selectivity for the desired opioid receptors.
Conclusion
Conversion of Salvinorin B to Amino-salvinorin
General Amide Coupling
Lifetime prevalence of mental disorders in US adolescents: Results from the National Comorbidity Survey Replication–. Opiate receptor: demonstration in nervous tissue. National Institutes of Health Pathways to Prevention Workshop: The Role of Opioids in the Treatment of Chronic Pain. The reward pathway and addiction | National Institute on Drug Abuse (NIDA) https://www.drugabuse.gov/publications/teaching-packets/neurobiology-drug-addiction/section-ii-reward-pathway-addiction/1-reward-pathway-addiction (accessed in April 22, 2019).
The G protein-biased κ-opioid receptor agonist RB-64 is an analgesic with a unique spectrum of activities In Vivo. Pharmacokinetics of the potent hallucinogen Salvinorin A in primates parallels the rapid onset and short duration of effects in humans.
