Help
Options
Didn't know it?
click below
click below
Knew it?
click below
click below
Don't Know
Remaining cards (0)
Know
retry
shuffle
restart
0:00
Embed Code - If you would like this activity on your web page, copy the script below and paste it into your web page.
Normal Size Small Size show me how
Normal Size Small Size show me how
MCPHS MEDCHEM I ex1
MCPHS - MedChem I Exam 1 (Stuff)
| Question | Answer |
|---|---|
| Approved Drugs ? | 370/10yrs at Cost $800 Million & takes 15 yrs. 10,000 Candidate compound with <10 going to Clinical Trials for 1 Approved New Rx. |
| What is "Medicinal Chem"? | Medicianal Chem is discovery, & design of new therapeutic chemicals turned into drugs |
| Pharmacology ? | Dymanics: Studies biochem & physiological effects of drugs on the body. Kinetics: Studies ADME of what the body does to the drug. Toxicology: study of adverse effects of drugs (beneficial or harmful) |
| Leads are...? | Optimised to yield "drug canditate" that can later become a "clinical" drug. |
| Hits come from? | passing screening assay with favorable results. |
| Compounds from Plants? | Alkloids (ephedra, cocaine), Glycosides (digitoxin), Steriods (mexican yams), essential oils (menthold, camphor) |
| Compounds from Animals? | Vitamins & Steroids |
| Compounds from Microrganisms? | Antibiotics (Pen) & Alkaloids (ergots) |
| Natural Compounds are? | More likely to be biologically active, easer to isolate comp. good starting point for semi-synth derivatives, generally more complex, & isometrically pure. |
| Natural Sources account for how much % of drugs marketed today? | 25% |
| Combinatorial Chem? | Synth of Libraries for Screening of biologically activity. Small number of precursors to generate a large number of compounds. |
| Libraries contain? | Family of comp. having sim. bases chemically |
| Combinatorial chemistry uses what instead of reaction wells to synth compounds? | Polystyrene beads that allow for easy isolation and purification of peptide & non-peptide libraries. Reactions are sluggish, hard to scale up, & diversity may not be equal to conventional synth methods |
| Peptide Libraries can be synth by what method of comb. chem? | "Split Synth" (10^4 to 10^6 made) 100-500 pmol obtained causing structure determination to be difficult/impossible. |
| Non-peptide Lib. made by comb. chem? | similar method as pep lib but, reaction rates may differ causing incomplete reations. Mixtures make accurate assaying difficult (false +/-'s) |
| Individual comp.'s can be synth by? | Parallel synth in tubes, but fewer coumpounds sysnth at one time (50 - 10^4), but more of each can be synth (1-50 mg). Can be built on privilege structures (as the scaffold). The design scaffolds based on structural motifs of the target. |
| Three Traditional Approaches to Bioassays? | Biochemical, Cellular, Whole Animal System Assays |
| Biochemical Assays are? | Receptor or Enzyme Inhibition/selectivity |
| Cellular assays are...? | 1.) Cell cultures to determine cell penetration, receptor activity, or transport. 2.) Isolated Tussues used to determine effects & possible toxicity 3.) Liver Tissue (microsomes) to determine metabolism & drug interactions. |
| Animal assays are ...? | used to determine toxicity, LD50, organ-specific efficacy, kinetics, dynamics, & models for clinical trials |
| High-Throughput Screening? | Rapid screening of 1,000's comp's (robotic = 100,000 comp/d). Limitation is Requires Efficient Assay to screen for hits (false +/-) |
| How can Hits be Accidentally discovered? | Chance (Pen & librium/chlordiazepoxide) & Observations durring clinical trials |
| Two Intentional ways to discover Hits? | Comp-Centered & Target-Centered Approaches |
| What is the shot-gun approach to ID Hits? | It is part of target centered approach. *(Comb-Chem then High-Throughput screening) |
| Target-Centered Approach is also known as? | Rational Drug Design |
| Compound-Centered Approach is also known as? | Random Screening |
| Comp-centered can do what for a single compound? | Determine multiple uses for one compound |
| Target-centered can do what for single medical need? | It can be used to ID many compounds that can be used for that one target |
| Compound-Centered appoach does what with skeleton structures? | It uses the skeleton structure of a natural agonist to be modified (adding groups) to desgn such things as blockers. An example is Histamine changed into Cimetidine as a Histamine Blocker |
| Likely hood of Hit from target-centered approach to be pharmacologically active? | More likely |
| Disadvantage of Target-Centered Approaches? | need to know the cystal structure of target before starting, and a large number of compounds must be screened. Spite this the crystal structure may not resemble what the target is really like in nature. |
| Drug-Receptor interactions are? | Lock & key model or Flexible Models |
| Why Flexible Moldels? | Result from conformational changes on binding. |
| What are receptors made from? | Proteins that form peptide bonds |
| What is the Identity distance of a peptide bond? | 3.61 Angstroms, and drugs have multiples of this distance between functional groups. |
| What is the distance between two turns of an alfa-helical structure? | 5.5 Angstroms (XR-(CH2)2-NR'2) |
| what is bond stregnth of ionic bond? | 5 kcal/mol (CH3-OH) |
| What is bond strenght of Dipole-Dipole and/or H-bond (R-H..O-R)? | 1-7 kcal/mol |
| What is bond strength of Van Der Waals'? | 0.5 - 1 kcal/mol |
| What is stregnth of Hydrophobic bond? | 1 kcal/mol |
| What is a Pharmacophore? | Small part of drug tha interacts w/ receptor. It is the group(s) that are responsible for receptor binding and are responsible for activity. |
| Auxophore? | Groups that may interfere with binding groups. These are generally modified. |
| How aer auxophores determined? | by sequentially cutting them off and testing for reactivity/affinity, or by the Andrews Method (calculating). |
| Andrew's Analysis says? | Activity and potency of drug is directly dependent on the interactions of pharmacophoric groups with receptors. |
| How is Andrews method used? | Binding Energy is calculated and compared with measured values. If low, the some functional groups are not binding. If High, then it is binding differently than what was anticipated. |
| Two basic types of drugs? | Structure specific and Structure non-specific |
| What are 4 mechanisms to change (increase) potency of structure? | 1,) Homologation 2.) Chain Branching 3.) Ring-Chain Transformations 4.) Bioisosterisms |
| Homologation ? | Comp's that differ by constant unit (CH2)n. Lengthing # from 1 to 5-9 CH2's can optimize the potency by increasing lipid solubility. Too long and it lowers water solubility to the point where drug is not active. |
| What does chain-branching do? | makes drug less lipophilic (kinetics) and/or can interfere with receptor binding (dynamics) |
| Ring-chain Transformation? | Can affect potency & safety by increasing lipophilicity and/or may enhance or constrain binding (similar to chain-branching) it may change activity. |
| BioIsosterism? | Substituents (groups) that have similar physical, chemical, and biological properties. |
| Classical Isosters? | Groups having same # valance elec, but diff. # of atoms (Identical peripheral layer of electrons). |
| Non-Classical Isosteres? | Do not possess features of classical isosteres, but they have similar biological activity. |
| Ring-chain trans equal what? | isosteric interchanges that can effect tox., activity, or kinetics |
| BioIsoSterism can have diff size, shape, elec distrib., lipid sol., pka's... BUt, the receptor interactions are generaly NOT? | Affected |
| Yet, BioIsosterism can have? | changes in activity, potency, or toxicity |
| Isomerisms affecting activity are? | Optical, Geometric, Conformational |
| Why do Isomerisms affect biological activity? | B/c of Differences in Physical parameters such as partition coefficient, pKa, selective ADME.... AND, the ability to BInd to Site of Action !!! |
| Optical Isomerisms are different how? | + (R) rotates Clockwise while, - (S) rotes light counter-clockwise. Changing this rotation may cause changes in Transport & Metabolism Selectivity, Isomers may bind to non-specific sites of action, or may bind differently ( - ephedrine is more active) |
| Geometric Isomers are? | Cis or Trans because of restrictive bonds |
| The geometric isomers of same comp. can change what? | The distance between groups and length of overall molecule. This changes the physical properties alot. |
| Conformational Isomer examples? | Eclipsed, staggered, chair, boat, twist... (Non-identical spatial arrangements of atomes in molecule resulting from rotation about carbon bonds that allow movement. |
| Conformational Isomers can be both what...? | Agonists or Antagonists depending on how they allign when binding to receptor |
| Example of conformational isomer? | ACh: Cis = nicotinic while Trans = muscarinic |
| Structure mod that INCREASE LIPOPHILICITY do what? | (Highly Increased Lipophilicity): Lower Oral Bioavailability, but increase metabolism & Plasma binding to proteins (Low Lipophilicity is usually more problematic with poor membrane permeability. |
| How is lipophilicity determined? | Hammett Equation: Log (K/Ko) = P*O (rho x sigma) *where, K is reaction rate constant for the "standard" compound, and Ka is the one you are measuring it against. |
| Elec Parameter (O, sigma) substit. const. depends on ? | electronic properties & position of substituents |
| More positie values of O (sigma) mean what? | The more pos. O (sigma) values the more electron withdrawing groups. |
| More negative that O (sigma) is...? | The more electron donating groups there are |
| Meta const. arise from what? | Inductive Effects only |
| Para const. arise from what? | Inductive & Resonance Effects |
| Reaction constant, P "rho" (slope) depends on what? | Type of reaction & reaction conditions |
| Large absolute values of P "rho" (slope) mean what? | Great sensitiveity to the effects of substituents |
| Negative P "rho" values (neg Slope) means what? | Reactions favor by electron donation |
| Positie P "rho" values (POS. Slope) means what? | Reactions favored by electron withdrawal |
| What is Hansch Hypothesis? | That a linear free-relationship exists b/w lipophilicity & biological activity, and that the measurement of lipophilicity Partition Coeffecient (P, "Pee") can be determined by the solubility in 1-Octanol vs. Water. |
| What is the equation for the Partitian Coeffient, P? | P={[comp]oct } / {[comp]aq x (1-alpha)} |
| What does alpha stand for in (1-alpha) ? | alpha is the degree of Dissociation of compound in water CALC from ionization constants (ionized = more water soluble) |
| How can you tell if a compound is more soluble in water? | P<1, or Log P <0 |
| How can you tell if comp is more soluble in 1-octanol? | P>1, or Log P>0 |
| What does in mean if Log P is approx. zero, or infinity? | That drugs (comp) is unable to cross the membrane |
| Hansch Proposal was? | That there is an optimum b/w water soluble (oral solubility/blood solu &activity) and lipophilicity (absorption ability to cross membrane / plasma protien binding & metabolism) |
| What is Log D? | Ionization is a function of pKa of comp & pH of solution, so Log D dscribes the Log P of an ionizable compound at a "particular" pH. Log D4.5 is Log P at pH 4.5 |
| When does Log D change? | Log D only changes with pH for ionizable compounds (only). If is not ionizable then Log D does not change with changes in pH! |
| Modification of leads should have Log D(Low pH of Stomach) <1 so that it is "more soluble in wather", what should Log D(with pH around 7 be for blood)? | It should change when entering the blood to a positive number for Lod D(+/- 7.5 pH). When Log P is >1 it is considered lipophilic and should then pass though the membrane if at the optimal for the type of membrane. CNS BBB has optimal Log P = 2. |
| What is the effect of electron withdrawing groups on leads? | Tends to Lower pKa, making acids more ionizable & bases Less Ionizable (Vise Versa for elec donating groups) |
| meta directing groups such as -COOH are "deactivating" to a ring pulling electrons away from the ring. What does this do to an acid compound? | Electron withdrawing groups make acids more ionizable. |
| What effect does an electron withdrawing group have on a Basic compound? | Withdrawing groups tend to make Basic compounds less ionizable. |
| What effect would electron donating group have on an acid? | elec donating groups make acids less ionizable. |
| What effect does an elec donating group have on a basic compound? | donating groups tend to make basic compounds more ionizable. |
| What is the Lipophilicity Constant? | Pi = Log (Px/PH) Where, Px is the Partition Coefficient of Compound substituted with X, and, PH is Partition Coefficient of Parent Compound (no substituent) |
| What are the properties of Pi? | Additive & Costitutive |
| What does additive mean for Pi? | Additive: multiple substituents exert influence equal to the sum of the individual substituents. |
| What does branching do to lipophilicity with respect to Pi? | Branching reduces lipophilicity by a factor of (0.2)n, where n is the number of branches |
| How is the lipophilicity affect of a substituent calculated? | Pi(Substituent) = Ave of all {Log P (substituted parent type) - Log P(each different parent type unsubstituted) |
| What does Constitutive mean for Pi? | Effects of substituents may differ depending on the molecule to which it is attached and the environment that is is in (e.g. Inductive effects...) Alkyl groups are the least constitutive. |
| How is the prediction calculation of a newly substituted parent compound calculated? | Log P = n1(Pi grp1) + n2(Pi grp 2) +....+ nN(Pi grp N) - nB(0.2 for Branches) |
| What effect do elec withdrawing groups "Inductive Effects" have on lipophilicity (ie Pi)? | Withdrawing groups increase Pi, this means that it increases lipophilicity, and decreases water solubility. |
| How does Resonance effet H-bonding of aromatic systems? | Resonance effects on delocalization of non-bonded electrons decrease H-bonding in aromatic systems |
| What effect does Resonance have on Lipophilicity? | It also increases lipophilicity |
Created by:
MCPHS
Popular Pharmacology sets