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Med Chem Exam 2
| Question | Answer |
|---|---|
| What is the mechanism of action of paclitaxel and colchicine | They bind to tubulin and block axonal transport (impedes neurotransmission) |
| What is the mechanism of action of local anesthetics? | Reversibly block NT through action within the Na+ ion channels of the axonal membrane in any type of nerve fiber (can inhibit catecholaminergic or cholinergic NT) |
| What are the two major functional groups of catecholamines? | Catechol group (ortho dihyroxybenzene) and beta-phenethylamine |
| Dopamine, NE, and Epi all contain 2 hydroxyl groups that are ___ WB? WA? And the order of pKa values from largest to smallest? | WA D-->NE-->Epi |
| NE and Epi contain a ____ ____ hydroxyl group that is ___ to the aromatic ring that is ___ acidic. | neutral secondary benzylic less |
| The amino groups of Dop, NE, and Epi pKa from largest to smallest? The amino group is ionized or unionized at physiologic pH? | Epi-->NE-->Dop ionized |
| Uptake of NT precursors is a possible mechanism. What is the precursor for all catecholaminergic NT that is actively transported into the axonal cytoplasm? | tyrosine |
| The first step in converting tyrosine into a catecholamine NT takes place in the neuronal cytoplasm. This rxn is catalyzed by what enzyme? What does this enzyme do? | tyrosine hydroxylase It adds a hydroxyl group (phenolic) onto the meta position of the aromatic ring resulting in a catechol |
| What is the rate-limiting step in catecholamine synthesis? | tyrosine hydroxylase |
| Tyrosine hydroxylase is controlled by 3 mechanisms: | 1) Phosphorylation/dephosphorylation of the enzyme provides rapid regulation of its activity 2) Enzyme undergoes feedback inhibition by catechol-containing cpds 3) The gene for tyrosine hydroxylase is regulated for longer term control of enzyme activity |
| What enzyme forms dopamine and what does the enzyme do? | L-aromatic amino acid decarboxylase it removes the carboxylic acid group as CO2 |
| How is NE formed? | It is formed from dopamine that is in storage vesicles. Dopamine beta-hydroxylase stereospecifically adds an R-absolute configuration hydroxyl group to the beta position (this is a benzylic OH) |
| How is Epi formed? | NE diffuses into the cytoplasm of the adrenal medulla. Phenylethanolamine-N-methyltransferase acts to methylate the nitrogen of NE with S-adenosylmethionine (SAM) being the methyl donor |
| Alpha-Methyl P-tyrosine Metyrosine (Demser) differs from tyrosine in what way? | There is a methyl group added to the para position (adjacent to the carboxyl and amino groups) |
| Alpha-Methyl P-tyrosine Metyrosine (Demser) is used to treat ____ and the mechanism of action is ____. | Pheochromactyoma Competitive inhibitor of tyrosine hydroxylase |
| What is unique about Alpha-Methyldopa (Aldomet)? | One of very few hydrates that is not a salt |
| What is Alpha-Methyldopa (Aldomet) mechanism of action and how was it formed? | Inhibits L-aromatic amino acid decarboxylase (also a substrate for the enzyme). Formed by adding a hydroxyl group to tyrosine |
| THE ADDITION OF A STERICALLY BULKY GROUP TO THE SUBSTRATE OF AN ENZYME (USUALLY NEAR THE ACTUAL SITE IN THE SUBSTRATE WHERE THE CHEMICAL CHANGE OCCURS) CAN RESULT IN AN INHIBITOR OF THAT ENZYME | |
| Alpha-methylNE is ___ with NE and its mechanism of action is ____. | Equipotent. It is an alpha2-adrenergic agonist in the CNS with antihypertensive activity. |
| THE STATED MECHANISM(S) OF ACTION OF MANY DRUGS CAN CHANGE AS NEW EXPERIMENTAL EVIDENCE AND EVEN NEW BIOCHEMICAL PATHWAYS ARE ELUCIDATED. THE OVERALL CLINICAL ACTIVITY OF MANY PHARMACEUTICAL AGENTS MAY BE A COMBINATION OF SEVERAL CONTRIBUTING MECHANISMS. | |
| Disulfiram (Antabuse) contains a ___ bond. The mechanism of action is ____. It is used to treat __. | disulfide Inhibits acetaldehyde dehydrogenase leading to an increase in acetaldehyde, which causes nausea, vomiting, palpitations, unconsciousness, death. alcoholics |
| Metabolism of ethanol | Alcohol dehydrogenase converts ethanol into acetaldehyde. Aldehyde dehydrogenase converts acetaldehyde into acetate, which becomes acetyl CoA. |
| Disulfiram (Antabuse) can also inhibit enzymes containing ___ groups. | Sulfhydryl (R-SH) |
| Disulfiram (Antabuse) is also a relatively nonspecific inhibitor of the microsomal enzymes involved in drug metabolism and can thus cause drug interactions. | |
| Disulfiram is a _____ of several metals, including the copper cofactor in dopamine Beta-hydroxylase. Inhibition of this enzyme can lead to ___. | chelator hypotension |
| A CHELATE (KELA=CRAB CLAW) IS A CYCLIC COMPLEX OF A MOLECULE WITH A METAL ION. ELECTRON RICH ATOMS SUCH AS O, N, OR S WEAKLY BOND TO THE E- DEFICIENT METAL ION. A DEPICTION OF THE DISULFIRAM CHELATE OF THE CU2+ ION IN DOPAMINE BETA-HYDROXYLASE HAPPENS. | THE CU2+ ION IS E- DEFICIENT |
| Storage of adrenergic NT aids in protecting them from both leakage and metabolic processes as well as from nonenzymatic oxidations. In an ATP dependent process, __ protons are released for each catecholamine molecule taken up. | 2 |
| The material contained in the storage vesicles are known as ____. | chromaffin granules |
| Constituents of chromaffin granules include: | 1) ascorbic acid may prevent/slow down catecholamine oxidation 2) Dopamine beta-hydroxylase 3) Other peptides (enkephalins, neuropeptide y) 4) ATP binds to the catecholamine |
| Why do 4 molecules of catecholamine bound to ATP? | The triphosphate portion contains 4 negative charges that are attracted to the positive charge of the positive amine of catecholamine |
| Which AA has an indol ring? | tryptophan |
| The pure alkaloid form of Rauwolfia Serpentina is: | reserpine |
| Rauwolfia Serpentina is a combination product with ____ | diuretics |
| Preparations of Rauwolfia Serpentina all inhibit the ___ ___ ___ of ___ and ___ into the storage vesicles thus depleting the neuron of NT. | ATPase dependent storage NE Dopamine (note: and maybe serotonin) |
| MANY COMPOUNDS WITH EXTENSIVE DOUBLE BOND CONJUGATION AND AN ELECTRON RICH CENTER CAN UNDER PHOTODEGRADATION. AS IS COMMON WITH MANY DRUGS WITH AN INDOLE, RESERPINE IS SUSCEPTIBLE TO DECOMPOSITION FROM LIGHT AND ALSO TO OXIDATION. | PREPARATIONS OF RESERPINE AND ITS ANALOGUES SHOULD BE STORED IN LIGHT RESISTANT CONTAINERS. |
| ___ does not contain the 11-position methoxyether group found in reserpine, but its phamacological actions are similar. | Desperidine |
| Guanethidine Monosulfate (Ismelin Sulfate) contains a tertiary amine and a guanadino group, which is ___ (a or b). It is used to treat ____. | basic moderate to severe hypertension and several types of renal hypertension ( associated with more SE) |
| Guandrel Sulfate (Hylorel) is a __ compound structurally, which causes is to be _____. It is used as a(n) ___. Its activity is decreased by compounds that ___. | spiro not be able to move around easily; usually in right conformation antihypertensive agent inhibit the neuronal reuptake of NE (tricyclic antidep, cocaine) |
| Guandrel (Hylorel) depletes the ___ stores from the ___. It also acts as a false NT that ____. | NE adrenal medulla blocks the adrenergic actions of NE (binds to rec., but won't activate) |
| THE TWO RINGS THAT SHARE A SIGNLE COMMON CARBON ATOM ARE SPIROS. GUANADREL IS A SPIRO KETAL. THE TWO RINGS ARE RIGIDLY FUSED PERPENDICULAR TO EACH OTHER. TROPSIUM CL (SANCTURA), CEVIMILINE HCL (EVOXAC) ARE ALSO SPIROS | |
| Originally developed as an ___, the use of bretylium tosylate was discontinued for this indication due to ____. Bretylium tosylate is now utilized as an ___. Its structure contains a ___, so it has no CNS effects and has ___ absorption. | antihypertensive agent erratic oral absorption and the development of tolerance Antiarrhythmic Quaternary amine Decreased and erratic |
| Adrenergic neurotransmitters are released by the same ___ dependent mechanisms as other neurotransmitters | Ca+2 |
| The catecholamine neurotransmitters bind to two general types of receptors and, therefore, can be characterized as: | 1.Dopaminergic - dopamine 2.Adrenergic - norepinephrine and epinephrine |
| subdivision of the adrenergic receptor family into a total of nine different subtypes: | Alpha 1a, 1b, 1d Alpha 2a, 2b, 2c Beta 1, 2, 3 |
| The adrenergic neurotransmitters bind to their receptor sites in a ___ manner through a collection of the weak binding forces described in your reviews. The receptors are what type? | reversible G-protein coupled (7 transmembrane segments) |
| In a G-protein, the ___ terminus is extracellular and the ___ terminus intracellular. | amino carboxy |
| The coupling of G-proteins is through ___ | conformational changes upon ligand binding |
| RECEPTORS OFTEN HAVE IC SECTIONS THAT ARE ANCHORED TO VARIOUS CELLULAR MEMBRANES VIA A FA, AN ISOPRENOID GROUP OR VIA A GLYCOSYL PHOPHATIDYL INOSITOL LINKAGE. THESE LIPOPHILIC GROUPS ARE GENERALLY IN A LABILE THIOESTER, OR GLYCOSIDIC LINKAGE OR THIOETHER | |
| PALMITIC ACID HAS A ___ LINKAGE. ISOPRENOID FARNESYL HAS A ___ LINKAGE. | THIOESTER THIOETHER |
| GLYCOSYLATED PROTEINS ARE BOTH SECRETED BY THE CELL AND FOUND IN THE CELLULAR COMPARTMENTS | These polysaccharides function in protein folding, stabilization of protein, anchorage to a membrane, recognition by other proteins |
| The human __ receptor has been on of the most studied adrenergic receptors. | β2 |
| The β2 receptor has __ sites of non-covalent bonding and those types of bonds are ___. | 3. Ionic bonding with the N of Asp-113. Hydrogen bonding with the O of ser-204 and ser-207. Van der Waals/hydrodphobic bonding on the benzene ring. |
| Average bond strength of an ionic bond is ___ kcal/mol. The average bond strength of a hydrogen bond is __ kcal/mol. | 5. 4. |
| A __ residue on transmembrane segment VI is thought to bond to the phenyl ring of epi, probably through van der waals or hydrophobinc interactions | phenylalanine |
| Average bond strength of hydrophobic/van der waals is __. | 4.5 |
| Average bonding energy for epi to a B2 receptor is about __. | 21.5 kcal/mol |
| G-protein activation process: | 1) drug binds to the G-protein 2) G-protein changes conformation 3) G-protein releases alpha-subunit to selectively activate one of the 2nd messenger systems (alpha subunit contains GTP, which when hydrolyzed prompts the subunits return) |
| Second messenger systems | 1) Adenyl cyclase forms cAMP 2) Guanylyl cyclase forms cGMP 3) Increase conc. of Ca2+ ions 4) Cleaves PIP2 to form IP3 and DAG 5) Modulation of sphingolipid, phospholipid levels |
| SAR for sympathomimetic agents. Beta-phenylethylamine: | Maximal activity is generally attained with a two carbon distance between the amino group and the aromatic ring (2 C between) |
| SAR for sympathomimetic agents. Substitution on the amino group: | As the size of the amino substituent increases, the Beta activity increases (NE (R=H < Epi (R=CH3) < Isoproterenol (R=CH(CH3)2)) |
| For SAR for sympathomimetic agents, Beta2 selectivity often occurs with ___ amino substituents in conjunction with other appropriate substitutions | larger (Isoproterenol has B1 and B2 activity, but Colterol has almost all B2 because it has a bigger substitution) |
| For SAR for sympathomimetic agents, Alpha activity is even more sterically dependent. The ___ the substitution on the amino group, the more selectivity for alpha activity. | Smaller (alpha activity is maximized in Epi, but is almost absent in isoproterenol) |
| R=CH3 has __ alpha activity in sympathomimetic agents | maximal |
| R=CH(CH3)2 has __ alpha activity in sympathomimetic agents | almost no. (all beta) |
| R>butyl group has __ agonist activity | no. obtains alpha 1 antagonist activity |
| For SAR for sympathomimetic agents, Substitution of a small alkyl group (generally CH3) adjacent to the nitrogen results in: | 1) steric inhibition of monoamine oxidase (MAO). 2)little or no effect on catechol-O-methyl transferse (COMT) activity i.e. α substitution only increases the duration of action of noncatechol- amines (not metabolized by COMT). |
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morganc2
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