Exam 3 - Proteau

Question 1

Know how to draw Acetylcholine

Answer 1

Yeah.

Question 2

Know how to draw Muscarine

Answer 2

Yeah.

Question 3

Know how to draw S-(+)-Nicotine

Answer 3

Yeah.

Question 4

Know how to draw Atropine

Answer 4

Yeah.

Question 5

Three components of ACh structure:

Answer 5

Acyloxy group Ethylene bridge Quaternary ammonium group

Question 6

The Four questions asked

Answer 6

Clarify his answers.

Question 7

Synclinal

Answer 7

Lowest energy.

Question 8

Antiplanar

Answer 8

Favored at Nicotinic.

Question 9

Anticlinal

Answer 9

Favored at Muscarinic.

Question 10

Synplanar

Answer 10

Highest energy.

Question 11

(+)Trans-ACTM

Answer 11

Cycloproyl ACh conjugate. Approximates anticlinal conformation. Equipotent to ACh at M-receptors. 517x greater than (-)Trans. Both (+) and (-)Trans weak at N-receptors.

Question 12

Cis form of Trans-ACTM

Answer 12

Cycloproyl ACh conjugate. Approximates synplanar conformation. Racemic mixture - no activity at M-receptors. Weak activity at N-receptors.

Question 13

Acetylcholine as a therapeutic agent:

Answer 13

Cholinergic Agonist. Non-Selective for N or M. Very short t1/2 - rapid hydrolysis by AChE. Limited use - injected into eye to induce miosis in surgery.

Question 14

Carbachol

Answer 14

Cholinergic Agonist. Carbamate in place of ester. Still non-selective. Longer t1/2 - Carbamate hydrolyzed slower. Orally bioavailable, but on poor and erratic absorption. - Due to Quaternary Ammonium.

Question 15

Acetyl B-methylcholine chloride (Methacholine chloride)

Answer 15

Muscarinic Agonist. Methyl group added to the B-carbon. Induces selectivity for M-receptors. Used as racemate: - S > R - S hydrolyzed 1/2 as fast as ACh. - R is weak AChE inhibitor.

Question 16

Acetyl A-methylcholine chloride

Answer 16

Nicotinic Agonist. Methyl group added to the A-carbon. Nicotinic selectivity - never been used as a drug. Illustrates a point.

Question 17

Bethanechol chloride

Answer 17

Muscarinic Agonist. Ester replaced with carbamate like Carbachol. Methyl on B-carbon like Methacholine chloride. Muscarinic selective. Fairly resistant to hydrolysis: - Longer t1/2. Racemic: S is active. Orally available, poorly absorbed - quat. ammonium. Used for non-obstructive urinary retention (after surgery usually).

Question 18

Muscarine

Answer 18

Muscarinic Agonist 2S,3R,5S-muscarine chloride enantiomer specifically. Fungal natural product. Oxygen present as ether rather than ester. Not used clinically.

Question 19

Muscarinic Agonist SAR

Answer 19

Nitrogen capable of positive charge. Alkyl groups on N not larger than size of methyl. Ether-like or Ester-like Oxygen capable of H-bonding. Two-carbon distance b/w Oxygen and Nitrogen.

Question 20

Pilocarpine

Answer 20

Muscarinic Agonist Plant natural product. - Natives of S.America chewed leaves to increase salivation. Doesn’t seem to fit SAR. Hydrolysis - Pilocarpic acid: Inactive due to: - (-) charge - rigid 5-membered ring. Epimerization - Enantiomer of the ethyl group conformation - Also inactive Hydrolysis in Vivo - t1/2 = 1hr. Used for Glaucoma - directly onto eye. Used for dry mouth.

Question 21

Cevimeline

Answer 21

Muscarinic Agonist. Tertiary amine this time - Okay b/c can be protonated. Sterically, the N-alkyl groups are similar to methyls. Selective for m1 and m3 Muscarinic subtypes. 2 stereocenters - 2 of 4 enantiomers used. t1/2 = 5hrs. No ester hydrolysis. Rather CYP 3A4/2D6 - Sulfoxide product.

Question 22

Atropine

Answer 22

Muscarinic Antagonist. A plant natural product of Atropa Belladonna or “Deadly Night Shade.” Tertiary Amine within the Tropine base Bulky ester group shifts its activity towards antagonism. Racemic mixture known as +/- Hyoscyamine. - Only the S-form is active. Hydrolysis of the ester leads to inactive product. CNS effects minimal at therapeutic doses.

Question 23

Hyoscyamine

Answer 23

Muscarinic Antagonist The (-)S-enantiomer of Atropine alone. Separate drug.

Question 24

Scopolamine

Answer 24

Muscarinic Antagonist Also a plant natural product - Datura Stramonium - AKA “Jimson Weed” or “Loco Weed” b/c of more CNS effects than atropine - people smoke it. - structurally can’t predict this: possibly due to h-bond b/w the N group and the Epoxide group. Structurally similar to Atropine S-enantiomer is active. Difference is the Epoxide group. - a generally reactive feature. - very rare to see in a drug compound. Produces CNS depression. Uses: Motion Sickness.

Question 25

Ipratropium bromide

Answer 25

Muscarinic Antagonist "Ip" for the isopropyl group. - Creates permanent + charge. - Similar potency as Atropine. Used to treat COPD and Allergic Rhinitis - Large portion of the dose is swallowed. - Quaternary ammonium: only 7% absorbed. - 50% of that excreted unchanged, also subject to ester hydrolysis. - t1/2 is 2hrs, therefore, and dosing is QID.

Question 26

Tiotropium

Answer 26

Muscarinic Antagonist "Tio" for Thiphene group. Derivative of Scopolamine - Has the Epoxide - N-group is methylated - Ester group is bulkier Thiophene 2-3% is orally absorbed - 74% excreted unchanged. - t1/2 is several days! - Qd dosing. Besides hydrolysis, also P450 metabolism: - Oxidation or Glutathione conjugation - At Epoxide group.

Question 27

Aclidinium bromide

Answer 27

Muscarinic Antagonist Thiophene group like Tiotropium. Lipophilic substituent on N - Quaternary Ammonium. Also long-acting: - t1/2 = 5-8hrs - dosed BID Limited oral absorption - only 1% excreted unchanged. - extensively hydrolyzed even though ester group is bulky. Works well in lung, not much systemic absorption, and broken down very quickly if it is - great drug.

Question 28

Umeclidinium bromide

Answer 28

Muscarinic Antagonist Key here is the placement of the Ester group. - Provides protection from ester hydrolysis. Negligible oral absorption. Also long-lasting: - Effects last longer than 24hrs. - t1/2 = 11hrs Metabolism: - CYP 2D6: not a major player, O-dealkylation. - Hydroxylation more importantly.

Question 29

Oxybutynin

Answer 29

Muscarinic Antagonist Selective for urinary bladder. Tertiary amine. Metabolism by CYP3A4: - N-desethyl metabolite: Secondary amine. - Active product - contributes significantly. Caution with CYP3A4 inhibitors: - Ketoconazole antifungal for example - Enhances effects of Oxybutynin - Lowering of dose may be needed

Question 30

Solifenacin succinate

Answer 30

Muscarinic Antagonist Selective for urinary bladder. X-group is a Carbamate - functionally equivalent. Two stereocenters: - Single 1S,3R' product used. Metabolism by CYP3A4, yields two products: - 4R-Hydroxy metabolite - N-Oxide metabolite - Neither contribute to action. - Used only at low doses when with CYP3A4 inhibitor.

Question 31

Tolterodine

Answer 31

Muscarinic Antagonist Selective for urinary bladder. Phenol-Hydroxyl group is "R3-like." Chiral molecule: R-enantiomer active. Two main routes of metabolism, both by CYPs: - CYP3A4: N-Dealkylation - inactive secondary amine, unlike with Oxybutynin. - CYP 2D6: Benzylic Oxidation - yields active HMT; contributes to overall activity. t1/2 = 7-8hrs. EM = 7-8hrs. PM = 18hrs.

Question 32

Fesoterodine

Answer 32

Muscarinic Antagonist Selective for urinary bladder. Prodrug - as a modified version of HMT. - Under goes ester hydrolysis to form HMT. - Conversion does not depend on CYP2D6. Once as HMT - Undergoes 3A4-N-dealkylation and 2D6-Oxidation. - No difference b/w EM and PM: t1/2 = 7-8hrs.

Question 33

Darifenacin

Answer 33

Muscarinic Antagonist Selective for urinary bladder. Modified phenyl ring. R3 carboxamide considered bioisostere of hydroxymethyl - Can H-bond. Metabolism by 3A4-N-Dealkylation and 2D6-Oxidation. - No active metaolites. - EM: t1/2 = 12hrs. - PM: t1/2 = 20hrs.

Question 34

Trospium chloride

Answer 34

Muscarinic Antagonist "Tro" - modified Tropine base Quaternary ammonium - safe from CYP; avoids interactions. Used orally b/c it is poorly absorbed... - 10% absorption. - Most of the rest is excreted. - t1/2 = 20hrs. Metabolism proposed to be mainly ester hydrolysis. Even though poorly absorbed; can be dosed appropriately b/c it is safe from CYP.

Question 35

Glycopyrrolate bromide

Answer 35

Muscarinic Antagonist 1961 - peptic ulcers. 2005 - chronic drooling in pediatric patients. 2015 - COPD; Seebri Neohaler and Utibron. 2016 - COPD; Bevespi Aerosaphere w/ formoterol. Turns out it has m1/m3 \> M2 selectivity.

Question 36

Tropicamide

Answer 36

Muscarinic Antagonist Mydriacyl, Tropicacyl - For eye exams. Pyridine group creates "tertiary-like" compound: has better absorption into the eye.

Question 37

Benztropine mesylate

Answer 37

Muscarinic Antagonist Antiparkinson agent. Need to cross BBB for CNS effects: - Tertiary amine - Non-polar cyclic groups - Ether group: lipophilic

Question 38

Biperiden hydrochloride

Answer 38

Muscarinic Antagonist Antiparkinson Agent. Need to cross BBB for CNS effects: - Tertiary amine - Non-polar cyclic groups - No X-group - Tertiary hydroxyl is sterically hindered; relatively non-polar.