Drug Development and Discovery | CancerQuest
The potency of fentanyl and carfentanil compared to morphine organic synthesis, which was responsible for ensuring that Taxol—a very important The most commonly used strategy is using structure-activity relationships. only be structurally related, but may also share activity on the same Structural simplification is of particular importance in library, which allows both correlation of this chemical space with the . nine-ring scaffold derived from the natural product morphine, and ends with a simpler one-ring scaffold. STRUCTURE ACTIVITY RELATIONSHIP Abdul Samad Dr. Syed . 17 TAXOL Taxol, paclitaxel, trade name taxol, by Dr. WALL and Dr. WANI.
Pain responses were evaluated measuring mechanical allodynia at various times post-surgery from 15 to minutes. We found that a morphine and oxycodone significantly reversed mechanical allodynia in a time- and dose-dependent manner; b neither maraviroc nor AMD had an effect by themselves; c addition of AMD significantly shifted both morphine and oxycodone dose-responses to the left 1. These results indicate that the combination of CRAs with opioids permits use of lower doses of the opioids to achieve an analgesic effect equal to that obtained with opioids alone.
Using opioids in lower doses has the potential to reduce unwanted side effects and the development of tolerance and dependence. All mice met criteria for acquisition by the final acquisition session.
A standard inverted U dose response was observed with no significant difference between groups. Computational modeling and analysis of Oxycodone metabolism suggest high-risk drug-drug interactions with commonly co-administered benzodiazepines Insiya Y. Oxycodone, indicated for the treatment of moderate to severe pain, is a commonly used opioid with an unfortunately high abuse potential and risk of death due to overdose. Adding to this crisis are drug-drug interactions DDIs that occur when patients are simultaneously taking additional medications.
Analysis of FDA Adverse Event Reporting Systems for oxycodone shows that most fatal outcomes involve concomitant use of other drugs, of which nearly half result from co-administration with benzodiazepines, commonly prescribed sedative-anxiolytics.
This study examined the interaction between oxycodone and Diazepam, as a result of their shared Phase I metabolism by the CYP 3A4 enzyme. The benzodiazepine diazepam is also a competitive inhibitor of CYP3A4. We hypothesized that concomitant administration of diazepam may affect the metabolism of oxycodone and may lead to increased or prolonged adverse effects of oxycodone.
Using pharmacokinetic PK data of oxycodone at different clinical doses, we obtained a PK simulation of oxycodone using a one-compartment model with first-order dosing and linear elimination. We then simulated the oxycodone concentration-time profile in the presence of diazepam.
Our simulation showed that in the presence of diazepam, levels of oxycodone and active metabolite Oxymorphone from CYP2D6 accumulate. Our quantitative simulations with clinical doses show potential DDI and overdose risk thresholds for concomitant oxycodone diazepam use. Such information raises awareness for healthcare professionals prescribing opioids with other medications in the current climate of the opioid crisis. In wild-type mice, systemic administration of SNC80 s. We further expanded our study by exploring conditioned fear, and found that SNC80 also decreased conditioned fear-potentiated startle FPS responses in wild-type mice.
However, clinical applications of KOR agonists are limited by side effects, including dysphoria, sedation, motor incoordination and psychotomimetic effects in humans, except for nalfurafine in most patients. Nalfurafine has been used in Japan for treatment of pruritus in hemodialysis patients.
We have previously found that in male CD-1 mice, nalfurafine produced analgesic and anti-scratch effects dose-dependently, like U50,H. However, at doses effective for analgesic and anti-scratch effects, U50,H, but not nalfurafine, caused aversion, anhedonia, sedation and motor incoordination. In this study, we demonstrated that U50,H, but not nalfurafine, promoted KOR phosphorylation at T and S in mouse brains as detected by immunoblotting with phospho-KOR specific antibodies.
Taken together, these data reveal a correlation between agonist-promoted KOR phosphorylation and behaviors considered to be detrimental side effects, such as sedation, aversion and motor incoordination.
These results also suggest that agonist-induced KOR phosphorylation in mouse brains may be used to screen for KOR agonists devoid of these side effects. However, readying vaccine candidates for human testing presents unique quality and regulatory challenges. This study first focused on optimization and characterization of a conjugate vaccine targeting oxycodone, and then applied this technology to formulate analogous heroin and fentanyl vaccines. To this end, several batches of an oxycodone hapten conjugated to GMP-grade keyhole limpet hemocyanin OXY-KLH carrier protein adsorbed on alum adjuvant were produced to test the effect of coupling reaction temperature, time, buffer composition, and protein: Small conjugates could be evaluated by gel electrophoresis and size exclusion chromatography but were not immunogenic while larger conjugates were immunogenic but their size could only be measured by dynamic light scattering DLS.
OXY-KLH purification using tangential flow filtration TFF, scalable was compared to ultrafiltration non-scalable and both elicited equivalent oxycodone-specific serum IgG antibody titers and blockage of brain oxycodone compared to control.
Following TFF, levels of residuals were negligible. An analogous fentanyl vaccine F-KLH showed efficacy in blocking fentanyl distribution to the brain in mice and rats. These data suggest that KLH-based opioid vaccines adsorbed on alum adjuvant are suitable for pharmaceutical manufacturing. Diarylurea-based allosteric modulators of the cannabinoid CB1 receptor: Structure-activity relationship studies on the pyrrolidinylpyridinyl group Thuy Nguyen1, Thomas F.
Decker1, Nadezhda German1, Charlotte E. Langston1, Jenny Wiley1, Brian F. Thomas1, Terry Kenakin2, Yanan Zhang1 1Research Triangle Institute 2University of North Carolina Chapel Hill Allosteric modulators have attracted significant interest in the modulation of the CB1 signaling for therapeutic benefits while avoiding the adverse effects associated with orthosteric ligands.
In our previous studies on the CB1 receptor allosteric modulator PSNCBAM-1 we have reported that the pyrrolidinyl ring is not required for CB1 modulation and the pyridinyl moiety could be replaced by a simple phenyl or substituted phenyl rings. Here we extended the structure-activity relationships of these diarylureas by introducing heterocyclic groups at the place of the pyridinyl ring of PSNCBAM Most compounds possessed low nanomolar IC50 values at CB1 receptor without any significant activities at the CB2 receptor.
Interestingly, this new series of compounds displayed signaling pathway bias and variations in cooperativities with the orthosteric agonist CP55, and antagonist SRA. These results suggest that the CB1 signaling could be fine-tuned based on the orthosteric ligands and signaling pathways. Bobeck1 1Department of Biology, Utah State University Morphine is one of the oldest, and one of the most commonly prescribed painkillers for acute and chronic pain despite detrimental side effects after long-term use.
Morphine functions as an agonist of the m-opioid receptor MOPrwhich is an inhibitory G-protein coupled receptor. In this study, we examine the molecular consequences of chronic morphine treatment in the mouse ventrolateral periaqueductal gray vlPAG which is a key brain region known to be involved in the development of tolerance. The purpose of this research was to investigate activation of different kinases within the vlPAG following repeated morphine treatment.
We also note that phosphorylated PKC tends to localize to the plasma membrane following morphine treatment. Further, we observed that phosphorylated PKA tends to localize to the nucleus and that there is a significant reduction in nuclear punctae of pPKA following morphine treatment.
In addition, we observed putative differential activation patterns of all three proteins along the rostral-caudal axis. However, the involvement of other G proteins to downstream signaling events has not been rigorously characterized. The milieu of G proteins within a particular cell type may greatly influence the pharmacological properties of opioid ligands. G-protein specific toxins and overexpression systems were used to selectively measure signaling through specific G proteins in each cell line.
The individual G proteins had different effects on the pharmacological properties of opioid ligands resulting in functionally biased KOR signaling. The detailed molecular events underlying its agonist-dependent regulation remain incompletely understood. Here, we generated a series of phosphosite-specific antibodies and examined agonist-induced NOP receptor phosphorylation. We found that agonist-induced phosphorylation occurs primarily at four carboxyl-terminal serine and threonine residues in human NOP receptor, namely S, S, T and S Agonist-induced NOP receptor phosphorylation proceeds with a temporal hierarchy, in which S appears to be the primary site of phosphorylation.
In NOP-eGFP mice, NOP receptor multisite phosphorylation and internalization occurred in a dose-dependent and agonist-selective manner that could be blocked by specific antagonists. A comparison of chemically distinct NOP receptor agonists revealed dissociation between G protein signaling and receptor phosphorylation. Together, we showed for the first time agonist-selective NOP receptor phosphorylation, in vitro as well as in vivo.
Diverse cell types within the vlPAG exhibit unique adaptations to membrane firing properties after inflammation. The vlPAG is a highly heterogeneous region with diverse cell types that have yet to be characterized fully in terms of their response to noxious stimuli and opioids.
Studies are examining whether inflammation-induced Fos expression labels sensitized vlPAG neurons at acute 2 and 24 hours and after persistent inflammation 6 days using Fos-GFP expression in Long-Evans rats. The effects of opioids on the intrinsic membrane properties of these cell types will also be examined. They produced robust opioid-mediated antihyperalgesic action in carrageenan-induced inflammatory pain and a limited non-opioid analgesia in neuropathic pain. The present study was aimed to assess their actions on CFA-induced monoarthritis model and formalin test.
In formalin test pain behaviors were counted from 0 to 60 min.
International Narcotics Research Conference
In formalin test only Ile-Pro-Ile was able to significantly reduce pain reactions of the 2nd phase but not the 1st phase. Our results are in agreement with our previously published work proving that the two DPP4 inhibitors could activate different analgesic pathways.
In both pathways endogenous opioid peptides are involved. The Ile-Pro-Ile activated analgesic pathway might play a role in controlling pain transmission in formalin test. The molecular background of these diverse effects need further elaboration. While detailed mechanisms underlying the sensory detection and spinal processing of nociception have been uncovered, it remains unclear how brain circuits transform this emotionally inert information into an affective pain perception. Injury-induced plasticity within affective circuits, such as the basolateral amygdala BLAmay lead to a miscoding of sensory information concomitant with the emergence of chronic pain.
To identify the principles of nociceptive information coding in the BLA, we used a head-mounted miniature microscope to monitor the calcium activity dynamics of individual BLA neurons in freely behaving mice presented with a diverse set of painful and innocuous stimuli. We tracked the longitudinal dynamics of BLA neural coding across 9, cells before and after the development of neuropathic allodynia from a peripheral nerve injury.
Silencing of this ensemble alleviated pain affective-motivational behaviors without altering the detection of noxious stimuli, withdrawal reflexes, anxiety, or reward. After the establishment of neuropathic pain, the ensemble representations of prior innocuous and noxious stimuli became more similar.
Collectively, our results identify a neural representation of nociception in the amygdala that is necessary for the instantiation of the negative affective qualities of acute and chronic pain. Endomorphin analog treatment expedites recovery from chronic inflammatory pain and protects against latent sensitization Amy Feehan1, James E Zadina1,2,3,4 1Tulane Brain Institute 2Department of Medicine Tulane University 3Department of Pharmacology Tulane University 4SE Louisiana Veterans HCS, New Orleans, LA Opioids are unrivalled for relief of moderate to severe pain, but in addition to well-known side effects, including abuse potential, opioids have also been shown to paradoxically cause pain sensitization over time, thus limiting their use.
For preclinical development, we wanted to test whether chronic drug administration, before or after inflammatory pain, would induce sensitization of pain, as morphine does. In the current study, adult male Sprague-Dawley rats were implanted with intrathecal catheters and administered drug via osmotic minipump for 5 days.
At this stage in the drug discovery process, most lead compounds are not selective enough for their target molecule. In order to increase their selectivity, medicinal chemists alter the compounds' structures according to predicted structure-activity relationships. If the alterations improve selectivity, the lead compounds may be able to move onto in vitro and in vivo testing in selected disease models.
The main difference between the two is the origin of the lead compounds. In natural drug discovery, the lead compounds come from natural sources i. Combinatorial chemistry is used in labs to create a large number of desired molecules. This method is an efficient way to make many new chemicals, but generates molecules that are less structurally complex than natural compounds.
A more recently developed synthesis technique is called DNA-templated synthesis. This novel method allows researchers to more efficiently screen for compounds with desirable interactions with other biomolecules and also produce compounds that may not be produced via standard techniques.
At this time, synthetic drug discovery has lower hit-rates via HTS because the products are not as diverse as those in natural products. Specifically, it is important to know how the drug is absorbed, distributed, metabolized, and excreted ADME.
The ADME test provides insight on what happens when to the drug in the body, a field of study called pharmacokinetics. Scientists optimize lead compounds by changing their structures and testing these variations called analogues.
Potent morphiceptin analogs: structure activity relationships and morphine-like activities.
If optimization is successful, lead compounds can continue on in the drug discovery and development process, where they become potential candidate drugs. Scientists must determine if the candidate drugs are safe for human testing, understand exactly how the drug works, and determine effective and efficient ways of producing large quantities of the candidate drugs - a necessary process if the candidate drugs continue onto the clinical trial phases.
Candidate drugs that pass safety tests are eligible for clinical trial applications. The FDA reviews all prior work to ensure that clinical trials will be reasonably safe and that there are no unreasonable risks.
The IRB reviews the clinical trial plans that detail how trails will be conducted, which institutions, researchers, and doctors will be involved, and the informed consent procedure.
If the IND application is approved, the candidate drug moves onto clinical trials. Drugs that work well in other animals may not work in humans or they may have side effects that may show up in humans but not in the test animals.
These trials also compare existing treatments to the new, test drug. Clinical trials are composed of several steps, or phases, described below. Phase 0 This phase is designed to eliminate certain candidate drugs that are deemed ineffective. This is done via "microdosing" - small doses of a candidate drug are given to a few human volunteers, and the drug's effects are analyzed.
The candidate drugs that pass this phase move onto phase I.
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Not all drugs go through phase 0 testing. A small group of human volunteers 20 to people is given the candidate drug and the drug's effects are analyzed. Scientists will study the pharmacokinetics ADME, side effects, desired effects, safe dosages, etc.
The candidate drugs that pass this phase can move onto phase II. The candidate drug's short-term side effects, risks, mechanism of action, drug efficacy, optimal dosages and treatment schedule are analyzed.
The candidate drugs that pass this phase move onto phase III. The information collected during this phase will help create the instructions for the drug's usage directions risks, potential interactions with other drugs, etc. The NDA is a collection of information that includes candidate drug studies, manufacturing proposals, and possible medicine labeling. The FDA, along with FDA-appointed experts, reviews the information to determine if the drug can be approved as a new medicine.
There are three possible outcomes: The FDA can approve the candidate drug as a new medicine.