Problem+Set+1

Problem Set #1 (Dr. Sheng; PSW481) Date of submission: 11/03/2009

A. Read the definition and underline the keywords Definition of Medicinal Chemistry by the International Union of Pure and Applied Chemistry (IUPAC):

“Medicinal chemistry concerns the discovery, the development, the identification, and the interpretation of the mode of action of biologically active compounds at the molecular level. Emphasis is put on drugs, but the interests of the medicinal chemist are not restricted to drugs but include bioactive compounds in general. Medicinal chemistry is also concerned with the study, identification, and synthesis of the metabolic products of these drugs and related compounds.”

B. Name the following functional groups (Afolayan, Cabral, Goodrich, Lee, Patel, and Snell) 1. Sulfoxide 2. Amido 3. Ether 4. Ester 5. Amide 6. Amidine 7. Sulfonate 8. Sulfone

C. Please draw the chemical structures of the following sulfur-containing groups (Afrane, Cardoso, Gossiho, Libera, Patel, and Sok) 1. Sulfityl 2. Sulfonyl 3. Sulfamoyl 4. Sulfinyl 5. Sulfoxidyl 6. sulfhydryl



(You can upload a word or pdf file here)

D. Explain the meaning of the following terms (Al-Ruthia, Cormier, Friesen, Dillon, and Zamoiski) a. **Conjugate base**: Is a substance formed when an acid loses a hydrogen ion. It is considered a base because it can gain a hydrogen ion to reform the acid.

b. **Covalent bond**: Is a chemical link between two atoms in which electrons are shared between them.

c. **Ionization**: Is the process of converting an atom or molecule into an ion by adding or removing charged particles such as electrons or other ions.

E. Why do most G-protein coupled receptors have 7 transmembrane domains? Why is it an odd number? Could it be a smaller number (i.e. 1, 3, or 5)? (Akwari, Caron, Guan, Liu, Patel, and Stevenson)

G protein receptors have extracellular region which is the amino terminal, it is the site for ligand binding; they also have intracellular region which is the carboxy end at the cytoplasm and it is the binding site for G protein. The receptor is an odd number in order to have two ends, one extracellular and another intracellular. It can not be a smaller number because each loop is responsible for a specific binding, such as: Serine, threonine residues and target for phosphoration.

F. With the graphic sketch of the nephron below, discuss the following issues. a. Name the major anatomic sections of the nephron.( Alberding, Carr, Guillemette, Loring, Patel, and Stover)



b. Discuss the functional roles of each section on renal filtration, reabsorption, secretion, and excretion of the following substances.(Aleksiewicz, Casavant, Haibi, Manouchehrian, Patel, and Sultan) 1. Water 2. Na+ 3. Protein 4. Glucose 5. Amino acid

The ultrafiltrate from the blood contains both waste and molecules like urea and other useful molecules like amino acids, glucose, and salt. Because the filtration process at the glomerulus is nonselective (except by the size of the particles), the proximal convulated tubule works to actively transport and reabsorb substances useful to the kidney such as glucose, amino acids, and salts back into the extracellular fluid via selective reabsorption Facilitates the reabsorption of water, which works by solvent drag to also facilitate the reabsorption of urea. This water moves into the ECF to maintain blood volume. This area is impermeable to salts. Facilitates the reabsorption of salt and to maintain the hypertonicity of the blood. It is impermeable to water. Facilitates the active transport of materials from the blood directly into the lumen, such as Hydrogen ions, creatinine, and drugs (such as penicillin) which is the process of tubular secretion. This maintains blood pH. This area of the nephron is responsible for excretion. It is responsible for the removal of water (depending on the amount of water reabsorption facilitated by antidiuretic hormone and aldosterone.) It can excrete very concentrated or very dilute urine. Several substances can be excreted from the blood such as hydrogen ions, drugs, and creatinine
 * Proximal Convulated Tubule (Selective Reabsorption) **
 * Thin Descending Limb (Reabsorption of Water) **
 * Thick Ascending Limb (Reabsorption of Salt) **
 * Distal Convulated Tubule (Tubular Secretion) **
 * Late Distal Tubule and Collecting Duct (Excretion) **

c. Major mechanisms of renal cell transport. (Anderson, DaCosta, Hannemann, McCarthy, and Raphael) 1) Tubular secretion, Glomerular filtration, reabsorption 2) Proximal- Na/H exchanger, Na/HCO3 co-transpoter, Na/glucose and amino acid co-transporter 3) TAL- Na/K ATPase; Na/K/Cl co-transport system 4) Distal Tublule- Na/Cl cotransport 5) Collecting Duct- Na/k and Na/H

G. Multiple choice questions 1. Which of the following ions contains no electrons? b. Cl- c. K+ d. Ca++ e. SO4++
 * a. H+**

2. In the following reaction, HSO4- acts as a(n)__. H3SO4+ + HSO4- ⇋ 2 H2SO4__ b. Acid c. Both a and b d. None of them Please justify your choice (Ali, Chau, Heinzelmann, Mathew, Patel, and Sylvestre) HSO4- accepts a proton to form H2SO4, making it a base.
 * a. Base**

__3. What is your undergraduate major?__ a. Chemistry b. Biochemistry c. Biology d. Physiology e. Pre-pharmacy f. Other(Please specify)___

H. Discuss the classification of diuretics (Almetwazi, Chen, Ho, McNeill, Patel, and Syoufjy) Diuretics are classified by their chemical class (Thiazides), MOA (carbonic anhydrase inhibitors and osmotics), site of action (loop diuretics), or effect on urine content (ptassium sparring diuretics).

I. Fill out the blank areas with appropriate key words (Ball, Decelle, Harkins, McMahon, and Sanford) Classes of diuretics Acting sites MOA Therapeutic uses Adverse effects Carbonic anhydrase inhibitors Thiazides and thiazide-like diuretics in patients with hypersensitivity to sulfonamides,skin toxicity, bone marrow suppression || electrolyte imbalances, GI/CNS adverse effects rare ||
 * **Classes of Diuretics** || **Acting Sites** || **MOA** || **Therapeutic Uses** || **Adverse Effects** ||
 * **Carbonic Anhydrase Inhibitors (acetazolamide)** || Proximal Convoluted Tubule || Inhibition of renal carbonic anhydrase of both membrane and cytoplasmic anhydrase. Decreases reabsorption of sodium bicarbonate || Edema (diuresis),Open-anglular glaucoma, altitude sickness, alkanize urine, treatment of epilepsy, familial periodic paralysis || Metabolic acidosis, allergic reactions
 * **Thiazides and Thiazide-like Diuretics** || Distal Convoluted Tubule || Inhibits Na/Cl symporter || Edema associated with heart and liver disease, CKD, decreases BP || Decrease glucose tolerance,

J. As shown in one of the slides in the class, more than 60% of H2O and Na+ are reabsorbed at the proximal tubule which is the major acting site of carbonic anhydrase inhibitors. This indicates that carbonic anhydrase inhibitors are the most potent diuretics. (Alsaedi, Colton, Ibrahem, Moore, Patel, and Tai) a. True Justify your choice: Carbonic anhydrase inhibitors have weak diuretic activity because the mechanisms further downstream from the proximal tubule will take place and the result will be such that most of the sodium and water will be reabsorbed.
 * b. False**

Reference: Foye's Textbook on page 725

K. Explain the meaning of the “lead compound” in drug design and discovery. Please give three examples. (Ameyaw, Condon, Ikonomu, Morgan, Patel, and Tashakor)

A lead compound is a prototype bioactive molecule for subsequent semisynthetic or total synthetic modification. In others words it is a coumpound that has pharmacological or biological activity and who chemical structure is used as a starting point for drug formation. We didn't find exact examples but we know that the lead compound for penicillin was discovered in microbes, digitalis was discovered from a plant and insulin was isolated originally from animals. Morphine's pharmacophore/structure has been used in search of a analgesic derivative with less harmful side effects and addiction potential (Foyes pg 47)

Foyes; textbook 13, and [])

L. Discuss the purposes of lead modification/optimization with your neighbors. (Anderson, Conti, Iromuanya, Morin, Patel, and Tchani) The purpose of lead optimization is to make minor structural modifications to an existing lead in an attempt to simplify the structure while retaining the desired biological action. Structure modifications may increase potency and therapeutic index, and increase oral bioavailability while decreasing side effects. (Dr. Sharma's notes 6/22/09; Foye's p. 47)

M. Discuss (Brainstorm) the strategies for lead discovery and lead modification with your neighbors. (Beaulac, Dominique, Huynh, Mitsopoulos, and Skidmore) - **High throughput screenings** – HTS - The process of using automated assays to search through large numbers of substances for desired activity. HTS has become major hit ID method/leads in medium and large pharma companies. Discovery begins with the ID and validation of the target. Hit discovery then results in sets of compounds that interact with the target. Bio screening = main technology used. - **Fragment-based lead discovery** (FBLD) Based on ID small chemical fragments, which may bind only weakly to [|biological target], and then growing them/combining them to produce a lead with a higher affinity. FBLD can be compared with [|high-throughput screening] (HTS). In HTS, libraries with up to millions of compounds are screened. In early phase of FBLD, libraries with a few thousand compounds screened. - Fragment hits are the optimum starting points for lead discovery and optimization []

N. Which class(es) of diuretics can cause hyperkalemia and which can cause hypokalemia (Asal, Danella, Islam, Myzyri, Pereira, and Thomas)
 * Potassium sparing diuretics can cause hyperkalemia while loop diuretics and thiazides can cause hypokalemia**

O. Discuss the roles of positions 3, 6, and 7 of the thiazide structure in determining the activity of thiazide diuretics. (Asante-Somuah, Dang, Jackson, Nammour, Peters, and Tolpa)

picture in Foye's text - chapter 27 page 728 [] The roles of positions 3, 6, and 7 on the thiazide structure determine diuretic activity. At position 3, substitution with a lipophilic group gives an increase in the diuretic potency. At position 6, an electron withdrawing group is necessary for diuretic activity (little diuretic activity is seen with an hydrogen atom or electron donating groups). Compounds with chlor- or triflouromethyl groups are hightly active diuretics. For example, triflouromethyl substituted thiazides are more lipid soluble and have longer a longer duration of activity. Replacement or removal of the sulfonamide group at position 7 produces compounds with little or no diuretic activity.

P. According to the Wikipedia, quinethazone is considered to be a thiazide diuretic. Is this true? Please justify your answer. (Aubin, Dauphinais, Jashari, Nayar, Potvin, and Tran) Yes it is true, quiethazone is a thiazide diuretic and treats hypertension Reference: (Wikipedia)


 * FALSE. Using a more reliable resource, like our textbook on page 730, you find that it is actually a thiazide-like diuretic. The characteristic 4-sulfone group is replaced with a 4-keto group. Since they have similar structures, in this case they have similar effects.

Q. Etiology of edema and hypertension (Belfiore, Dufresne, Johnson, Ndungi, Nguyen, and Smith) Edema - Sodium and water retention often caused by heart, kidney or liver disease Hypertension - Primary hypertension has no known etiology by definition. However excess salt consumption, age, obesity, smoking, and genetics may be contributory factors. Secondary hypertension is directly related to another disease, ie renal dysfunction.

R. Why do most thiazide diuretics have weak carbonic anhydrase inhibitor activity? (Badavas, Davis, Jorgensen, Nelson, Pratt, and Vakil) ** Most thiazide diuretics have weak carbonic anhydrase inhibitor activity because they contain a sulfonamide group which is required for binding to the carbonic anhydrase enzyme.**