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MCPHS MEDCHEM 1 E2
MCPHS - MedChem I Exam 2 (b)
Question | Answer |
---|---|
What is the sequence off events that occur with mechanisms of action of drugs? | Endogenous ligand or Drug, Molecular = target, Cellular = Signal Transduction, Tissue = alt. Function, System = alt. Parameter |
Example of NO (Nitric Oxide) mech. of action? | NO, Stim: Guanylate Cyclase, Increases Cyclic GMP, Smooth Muscles Relax, Decreases BP |
What kind of targets are there? | Specific (Quinine elim Plasmodium) reduced Fever, Non-Specific (Tylenol Re-Set Temp Reg Center, but no cure) lowers Fever only, Both = Tx's Sx & Cures Disease (Quinine also resets Temp Reg Center, so it does both) |
How many diseases actually cured? | 26, so Tx'ing Sx's most of the time |
Where are targets located? | Extracellular, Cellular, Intracellular |
example: Extracellular? | Heparin & coagulation proteins, Ca/Mg Caronate & HCl (effect: decrease clotting or stomach acidity) *(Mech. of Action: Neutralization of co-agulation protiens or neutralization of Hydroprotic Acids) |
What are Targets? | Enzymes, Carrier Molecules, Ion Channels, Receptors (The Nature of all these targets is that they are all proteins) |
example: Enzymes? | Nitric Oxide on guanylate cyclase, or captopril on Angiotensin Converting Enzymes (ACE) |
example: Carrier Mol? | Reserpine on Catecholamine trans, Omeprazole on Proton Pump (Inhibits Na/H pump) |
example: Ion Chan? | Nifedipine on Ca chan.'s, General Anesthetics on K chan.'s |
example of Cellular Targets? | Ach on Ach Rcptr (effect: Contraction of muscle) Curar on ACh Rcptr (effect: Prevents Muscle Contraction) |
example of Intracellular Targets? | Sulfa Drugs (effect: Inhibit bac growth), AntiCancer Drugs (effect: Inhibition of cell replication) |
example of Receptors? | ACh on Nicotanic & Muscarinic Rceptrs, or N.E. on alfa & beta Rcptrs |
Who introduced the concept of "Receptive Substance"? | John Langley (1878) |
Who coined the term "Receptor"? | Paul Ehrlich (1909) Drug = 1st Messenger & Stimulated Effects inside a cell are caused by 2nd Messenger |
Definition of Receptor? | Macromolecular component of a cell that interacts w/ a drug and initiates the chain of events leading to the drug's observed effect. |
Where may Receptors be present? | Cell Membranes (Dopamine, ACh Rcptrs), Cytoplasm (Glucocorticoid), Nucleus (Steroid Hormone Rcptrs) |
What do Drug-Receptor Interactions do? | Signal transduction (Simulates or blocks endogenous signaling) |
What does Imantinib do? | It is a cancer drug that Inhibits Phos.- Kinase by binding with AA residues with many weak vander wall and H-bonds Similar to the way enzyme-substrates interact |
Drug-Receptor interactions resemble? | Enzyme-Substrate Interactions |
Intial therory of Drug-Receptor Interactions ? | Lock & Key Static Fit Model |
New Dynamic D-R Interaction Therory? | Induced Fit Model (Dynamic Interactions = both able to conform a little to accomodate the other) |
What is the name of receptor changes in shape? | Induced optimal binding by ligand |
Four Types of Receptors? | Ligand-Gated (Chollnergic Nicotinic Rcptrs), G Protein-Coupled Rcptr (alpha & beta Adreno-Rcptrs), Enzyme-Linked Rcptrs (Insulin Rcptrs), Intracellular Rcptrs (Steroid Rcptrs) |
What are Ligand-Gated Ion Chan Rcptrs Also Called? | Channel Linked Receptors |
What do Chan. Linked (Ligand-Gated Ion Chan.) Receptors do? | Cause changed in Ionic Membrane Potential |
What are G-Protein Coupled Rcptrs also Called? | G-Protein cpld rcptrs AKA "Metabotropic Receptors" |
What do G-Proteins Coupled Receptors do? | G-Pro Cpl'd Rcptrs Phosphorylate Proteins |
What do Enzyme-Linked Rcptrs do? | Protein & Receptor Phosphorylation |
What do Intracellular Rcptrs do? | Protein Phosphorylation & alt. Gene Expression |
How many times does G-Pro-Cpl'd Rcptrs Span the Membrane? | 7x's |
how many time does Enzyme Linked Rcptrs Span the Membrane? | 1x |
What kind of Responce does Ligand-Gated Ion Chan. (Chan. Linked) Rcptrs have? | Ligand-Gated respond RAPID/FAST (milliseconds) |
What are some examples of Ligand-Gated Ion Chan.? | nACh, GABAa, NMDA, Glycine rcptrs |
What is the structure of Ligand-Gated Ion Chan? | "Oligomeric" 5 subunits (2 alpha, 2 beta, 1 gama) can be in any order |
What are some functions of Ligand-Gated Ion Chan? | Neurotransmission, Cardiac Conduction, Skeletal Muscle Contraction |
What do alpha subunits tell you about the number of binding sites? | alpha subunits = # of binding sites on Ligand-Gated Ion Chan. |
How many Trans-Membrane (TM) domains can a subunit be made out of? | 4 TM domains per subunit, where TM2 compose the inside gates of the ion channel |
When ligand binds to ion chan rcptr what does it do? | Causes "Conformational" change in gate/pore by rotating the subunits |
Where are Nicotinic ACh (nACh) Rcptrs found? | nACh rcptrs found on NeuroMuscular (NM), Autonomic Ganglia (AG), & CNS |
How many ACh's does it take to open ion gate of nACh gate? | 2, the first one promotes binding of another mol. to 2nd. Known as "Receptor Cooperativity" |
What is ACh on nACh gate? | ACh is a skeletal muscle stimulator |
Why is ACh a stimulator on ion gate? | opens gate causing Na+ to move in depolarizing neuron |
Where are GABAa receptors found? | GABAa rcptrs are found in CNS (Spinal Cord, hypothalamus, hippocampus, substantia nigra, cerbral & cerebellar cortex) |
What Ion moves down gradient thru GABAa channels? | Cl- moves thru GABAa chan. to Hyperpolarize inside of nueron (inhibiting AP's) |
How do GABA a receptors interact with Benzodiazepines & Barbiturates? | Benzodiazepines & Barbiturates = Allosteric Modulation w/ GABAa |
What is the effect of Cl- moving in to CNS via GABAa? | Decreased Anxiety/Convulsions |
What is the structural shape of GABAa? | Pentameric |
Where are agonist sites located on GABAa? | Between alfa & beta subunits |
where are benzodiazepine binding sites on GABAa? | between alpha & gama subunits |
What does Y205 stand for ? | Y205 = Tyrosine (Beta Subunit) |
What does F65 stand for? | F65 = Phenylalenine (alpha Subunit) |
What are Tyrosine & Phenylalenine responsible for in GABAa? | The AA responsible for binding |
How many Binding Domains on G-Protein Coupled Rcptrs "Metabotropic"? | 2 binding sites on G-Pro Cpl'd Rcptrs (outside for Ligand, Inside for G-protein) |
What is structure of G-protein coupled receptors? | Seven transmembrane Alpha-Helices |
Why is the receptor called G-Protein Coupled? | G-Protein coupling domain protein is "Guanine-nucleotide bound) |
What are the G-Proteins made up of? | "HeteroTrimeric" = 3 subunits: alpha, beta, gama (one ea.) Alpha subunit binds to GDP, and Beta-Gama dislocate on outter membrane for other effects) |
What does activation of G-Pro Cpl'd Rcptrs produce? | 2nd Messengers |
What type of Response rate is observed w/ G-Pro Cpl'd Rcptrs? | "fast" but slower than GABAa. (sec to min) |
Where aer G-Pro Cpl'd Rcptrs found? | Ubiquitous: mAChR, Rcptrs of Catecholamine, Serotonin, Opioids, Peptides... |
When Agonist (Hormone/N.T.) binds w/ G-Pro Cpl'd Rcptr what happens? | Agonist bind on extracellular side of Membrane, Gs Protein exchanges GTP-GDP activating, Alpha-GTP subunit moves thru membrane to activate Adenylyl Cyclase, ATP converted to cAMP & PPi, Beta-Gama have other effects |
what happens when Agonist is no longer attached to G-Pro Cpl'd Rcptr? | Rcptr Reverts to Resting State, Alpha-GDP subunit back in place with Beta-Gama, Adenylyl Cyclase is Inactive |
How many Muscarinic receptor effects ? | 5 based on the types of G-Proteins they have |
Can one Agonist have more than one effect? | yes, by binding with different types of Muscarinic receptors |
What is Amplification of signal? | Cascade effect caused by G-Protein activation producing stronger effect inside cell |
Albuterol is? | Beta 2 Agonist Stimulating Adenylyl Cyclase to make cAMP that amplifies PKA causing protein phos. that cause bronchial muscles to relax |
Bethanechol is? | mAChR Agonist that activate Ca++ release via IP3 and Activated PKC by protein phos. that changes Tone of Bladder |
What does Gs (G-Stimulatory) do? | Activates Ca chan's & Adenylyl Cyclase (Blocked by Cholera Toxin) |
What does Gi (G-Inhibitory) do? | Act K+ chan's, Inhibits Adenylyl Cyclase (Blocked by Pertussis Toxin) |
What does Go do? | Inhibits Ca Chan's (Blocked by Pertussis Toxin) |
What does Gq do? | Activates Phospholipase C |
What does G 12/13 do? | Diverse Ion Transporter Interactions |