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74 Cards in this Set
- Front
- Back
Induction and resonance withdrawers
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nitro, ester, aldehyde, ketone, sulfinyl, sulfone
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Ortho/Para resonance and induction effects
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induction is only an issue in ortho
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Induction versus resonance
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Resonance will be the stronger of the two except when the attached is a halogen. Induction trumps resonance donation in a halogen.
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Resonance electron donator
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1st atom attached to the pi electron system has a lone pair in an sp3 orbital and isn't attached to a withdrawing group.
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Examples of resonance electron donators
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alcohol, ether, amines, sulfhydryl, sulfides
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-Is
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Inductive electron withdrawing group. Includes heteroatoms and cations.
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Examples of -Is
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nitro, sulfoxide, sulfinyl, ester, aldehyde, ketone, alcohol, ether, amine, quat ammonium
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+Is
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Inductive electron donating group. 2 types: alkyl groups and anions
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What factors can keep an acid base incompatibility from occuring?
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1. the acid and base reactants have enough polar groups to keep them in solution after reaction
2. dilute concentration 3. pH buffered so that they remain h2o soluble and ionized |
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Arrhenius acid/base
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acid is a proton donor, base is a hydroxide donor
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Lowry-Bronsted
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acid is a proton donor, base is a proton acceptor
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Lewis acid/base
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acid is an electrophile, accepts an electron pair.
base is a nucleophile, donates an electron pair |
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Basic salt
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free acid reacted w/ a metal hydroxide. ph-pka=log i/u
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Acid salt
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free base reacted with an organic or inorganic acid. ph-pka=log u/i
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Unionized neutral functional groups
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aldehyde, ketone, ester, amide, alcohol, tertiary sulfonamide, tertiary imide
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Phospholipase A
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effector of the second messenger arachidonic acid
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Phospholipase C
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effector of the second messengers IP3, DAG, and Ca2+
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cGMP
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second messenger of guanylate cyclase and phosphodiesterase
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cAMP
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second messenger of adenylate cyclase
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Ternary complex
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Receptor, ligand, and G protein. Intracellular amino acids attract G protein to bind after ligand induces conformational change. Message is received by G protein in this instant.
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GPCR of Gs versus Gi
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Gs has a long carboxy terminus and a short 3rd intracellular loop. Gi is the opposite.
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Example of Gs
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adrenergic receptors
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Example of Gi
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muscarinic and adrenergic receptors
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Gt
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Effector: phosphodiesterase
stimulates cGMP degrading |
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Go
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Effector: ion channels
inhibit Ca2+ |
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Gq
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Effector: phospholipase C
stimulates IP3, DAG, Ca2+ |
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Gi
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Effector: adenylate cyclase
reduces cAMP production |
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Gs
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Effector: adenylate cyclase
increases cAMP production |
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GPCR carboxy terminus
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Intracellular domain. ARG in 2nd loop activates intracellular receptor to attract G protein to 3rd loop for binding to another ARG after LEU in membrane triggers it.
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LEU residue in GPCR
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In helix 2 of transmembrane portion. Conformational change with ligand binding turns on ARG switch in intracellular domain. Critical to ternary complex formation.
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GPCR transmembrane domain
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Substrates actually bind to embedded residue and must be lipophilic enough to do this. Receptor is amphiphilic. Passes membrane 7 times.
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GPCR receptor amino acids
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PRO scattered throughout, ASP helix 3, SER helix 5, PHE helix 6, LEU helix 2
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PRO in receptor
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Form a pocket for ligand binding
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ASP in receptor
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anionic, binding site for cations
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SER in receptor
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hydrogen bonds
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PHE in receptor
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binds aromatic rings (van der waal's)
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GPCR amino terminus
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Extracellular domain. Regulate receptor conformation and overall function. ASN and CYS are key.
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CYS in amino terminus
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disulfide bridge links 2 from 1st and 2nd extracellular loops. provides rigidity and is critical to function
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ASN in amino terminus
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key sites for glycosylation, which regulates conformation and receptor function
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G protein
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Free in cell until ligand bonds receptor and throws the ARG switch attracting it. Ternary complex forms, GDP splits off, GTP binds. Mg2+ dependent process.
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G protein subunits
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alpha, beta, gamma. alpha loses affinity for beta and gamma when GTP binds.
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alpha subunit
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carries message to effector. when message transferred gtpase activity hydrolyzes GTP to GDP to shut off.
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Steps in GPCR
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drug-receptor-G protein-effector-biochemical activity
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Bioisoster of COO-
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SO2NH-
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Bioisosters of O
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CH2
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Bioisosters of S
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CH2CH2
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Bioisosters of C=O
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C=N, C=C, S=O, C=S
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Bioisosters of OH
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NH and SH
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Bioisosters of Cl
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Br and CF3
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Bioisosters of C=C
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NH2
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Bioisosters of cyclohexane
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cyclopentane
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Bioisosters of benzene
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pyridine and thiophene
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Bioisosters
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Functional groups w/similar electronic and steric properties. Exchanging them results in similar biological activity and retained affinity.
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Hydrophobic interactions
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driving force is increase in entropy in water and whle system. carbon rich, lipophilic alkyl chains, alicyclic rings, aromatic rings. weakest interaction
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van der waals
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induced dipole-induced dipole, pi stacking. distance dependent
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pi stacking
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2 aromatic rings approach, p electrons on one move to the other side to avoid the electrons on the other. a dipole is induced. the flat molecules stack.
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common unionized groups in an ion-dipole bond
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carbonyl, amino, imino, hydroxy, ethers, sulfhydryl
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groups in ion-ion bonds
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protonated amines (cationic), quat ammonium (cationic), carboxylate anions, primary and secondary sulfonamides (anionic), secondary imides (anionic)
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amino acid residues in receptors that react with anionic drugs
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ARG,LYS, HIS
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amino acid residues in receptors that react with cationic drugs
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ASP, GLU
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Optically active compounds
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+ dextrorotatory, rotates polarized light to the right
- levorotatory, rotates polarized light to the left |
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Major difference between diastereomers and entantiomers
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enantiomers are identical in physical and chemical properties (mp, bp,solubility)Diastereomers aren't.
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Diastereomers
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2 or more stereocenters in a molecule. n^2 number. R,R and R,S and S,R and S,S etc.
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Enantiomers
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non-superimposable mirror images. R and S or R,R and S,S etc.
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E
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2 highest priority groups on the opposite sides of a double bond. when there are more than just 2 groups
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Z
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2 highest priority groups on the same side of the double bond. when there are more than 2 groups
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Aniline
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N is conjugated to the ring but not a part of the ring or its aromaticity. weakly basic
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DNA based receptors
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Antibiotic anti-cancer drugs insert themselves into uncoiled DNA
Nitrogen mustard anticancer agents bind DNA Steroid hormones |
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Steroid hormones
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bind HRE (hormone responsive elements) in cell nucleus. first bind receptor in cytosol and the whole complex enters nucleus and binds HRE
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Tyrosine kinase receptor
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phosphorylates OH on TYR of other enzymes & proteins. extracellular amino terminus has cysteine disulfide bridge. glycosylation. autophosphorylation of TYR on the kinase activates it.
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Calcium channel blockers
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bind inactivated calcium ion channel in vascular smooth muscle. stabilizes it to inhibit Ca2+ flow for an antianginal, antihypertensive effect. verapamil and diltiazem interact w/ open channels for antiarrhythmic and cardiodepressant action
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imides
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secondary is acidic
tertiary is neutral |
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sulfonamides
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primary and secondary are acidic. tertiary neutral
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amino acids that participate in ion-ion bonds
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ASP (anionic), GLU (anionic), ARG(cationic), LYS (cationic), HIS (cationic)
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