Intro to lead compounds Flashcards
What is a lead compound?
A lead compound is a chemical entity with pharmacological or biological activity that serves as a starting point for drug development. It is typically modified to enhance specific parameters and may lead to structurally related drugs. A lead is rarely the exact structure that reaches clinical trials or the market but is valuable as a starting point in drug development.
Why are lead compounds financially valuable?
Lead compounds represent the foundation for developing new drugs, offering significant potential for commercial success. Their activity against disease-related targets makes them promising assets in drug development, capable of generating valuable patents and marketable drugs.
Describe the Vicriviroc story as an example of a lead compound development.
Vicriviroc was developed by Schering-Plough as a lead compound for HIV treatment through high-throughput screening. Initially a potent M2 antagonist with modest CCR5 activity, its structure was modified to improve CCR5 receptor selectivity while reducing affinity for the hERG ion channel, which decreased toxicity and enhanced its potential as an HIV therapeutic.
Can a lead compound lead to drugs in multiple therapeutic areas? Provide an example.
Yes, a single lead compound can generate drugs for different therapeutic classes. For example, Prontosil, originally developed as an antibacterial, led to the development of sulfonamides used in loop diuretics, hypoglycemic drugs, and carbonic anhydrase inhibitors.
What are the main sources of lead compounds?
Lead compounds can come from various sources, including natural products, libraries of synthesized compounds (combinatorial chemistry or fragment-based drug design), high-throughput screening, rational drug design, structure-based drug design, modification of endogenous agents, me-too drugs, and serendipitous discovery.
Give examples of drugs derived from natural products.
Examples include: Warfarin and Heparin (anticoagulants), Opiates (analgesics), Statins (cholesterol-lowering agents), Vinca alkaloids, Paclitaxel, and Etoposide (anticancer drugs), Artemether (antiparasitic), and numerous antibiotics.
What was the significance of Ephedra sinica in traditional medicine and modern drug development?
Ephedra sinica, also known as Ma-huang, was used in traditional Chinese medicine to treat allergies, asthma, and flu. Its active component, pseudoephedrine, became the basis for the decongestant Sudafed and is a controlled precursor for methamphetamine synthesis.
Describe the historical significance of Eber’s Papyrus.
Dating back to 1550 BC, Eber’s Papyrus is one of the oldest pharmaceutical records, detailing 800 prescriptions and 700 drugs. It included treatments for asthma, protective mixtures for clothing, and various herbal remedies, reflecting ancient knowledge of medicinal plants.
How did cocaine lead to the development of local anesthetics?
Cocaine, isolated from coca leaves by Albert Niemann, was the first effective local anesthetic, used for corneal anesthesia by Karl Köller. However, due to its addictive and cardiotoxic properties, its structure was simplified, leading to safer alternatives like procaine.
What is the origin of morphine, and what are its key pharmacological features?
Morphine, isolated from opium poppy by Friedrich Setürner, is a potent agonist of µ-opioid receptors with analgesic properties. It produces euphoria, making it addictive, and can cause respiratory depression, constipation, and tolerance. Morphine’s structure includes a phenolic OH, aromatic ring, and tertiary amine, which are central to its pharmacophore.
How does heroin differ from morphine, and why is it more potent?
Heroin, synthesized by C. A. Wright, is more lipid-soluble than morphine due to its ester groups, enabling it to cross the blood-brain barrier more easily. It is 2-4 times more potent than morphine and was initially marketed as a non-addictive alternative for pain and cough but was later controlled due to high addiction potential.
What is immunopharmacotherapy, and how does it relate to the opioid crisis?
Immunopharmacotherapy involves vaccines that stimulate the immune system to produce antibodies against specific drugs, like opioids. These antibodies form drug-antibody complexes that cannot cross the blood-brain barrier, potentially reducing the risk of overdose. This approach is under investigation for opioids, cocaine, and methamphetamine.
What are psychedelics, and how are they being explored for mental health treatment?
Psychedelics, such as LSD, psilocybin, and ayahuasca, alter sensory perception and thought processes. They are being researched for their potential in treating neuropsychiatric disorders and substance use due to their effects on serotonin receptors, particularly 5-HT2A.
Describe the therapeutic effects of psilocybin.
Psilocybin, a compound in “magic mushrooms,” is being studied for treating major depressive disorder. Clinical trials show that psilocybin therapy can produce rapid and sustained antidepressant effects, though it may require the psychedelic “trip” experience to achieve these outcomes.
Explain the differences between THC and CBD in cannabis.
THC is the psychoactive component that activates CB1 and CB2 receptors, leading to increased appetite, pain relief, and altered cognition. CBD, a non-psychoactive compound, acts as a negative allosteric modulator at CB1 and is used for conditions like epilepsy and anxiety.
