Medicinal Chemistry: Drug-Receptor Interaction

• The practice of medicinal chemistry is devoted to discovering and developing new drugs.
• In drug discovery, consider both the drug itself and its receptor.

Drug - Receptor Interaction

• Structural and Chemical Class / Drug Examples:
  • Barbiturates and Benzodiazepines: Anxiolytic, Sedative, and Hypnotics, working on GABA receptors.
  • Penicillin and Tetracyclines
  • Morphine affecting μ receptors.
• Three-Dimensional Shape of the Molecule relates to the drug’s function.
• Chemical Binding Involved: Heparin (base) + Protamine (acid) results in Neutralization.
• Structural Activity Relationship (SAR) relates structure to drug action.
• Isosteres: Compounds/groups of atoms share electron arrangement. Example: R–OH (alcohol) and R–SH (thiols).
• Metabolism, aka Biotransformation, converts drugs to polar, water-soluble metabolites, often making them inactive (nontoxic).
• Prodrugs: Inactive until metabolized into active agents (example: enalapril to enalaprilat).
• Chloramphenicol Palmitate is a prodrug masking bitterness of chloramphenicol. Palmitic acid masks taste as chloramphenicol is water soluble.
• First Pass Effect: Drugs from the GIT → Portal vein → Liver → Enzymes → Inactive Metabolites. Metabolism happens before drug reaches the system.

Phases of Metabolism

• Phase I / Functionalization introduces polar groups (OH, COOH, NH2, SH).
  • Accomplished through direct introduction of polar groups and/or modifying existing functionalities, like Redox reactions, Hydroxylation, Epoxidation, Reduction of Ketones, Aldehydes, Acids, Reduction of Nitro, Azo, and Azido Groups.
• Oxidation is common using the mixed function oxidase system and cytochrome p450 to attach oxygen. CYP3A4 is a most dominant isoform
• Reduction acts on Carbonyl (C=O), Nitro (NO2), and Azo (N=N) compounds, yielding alcohol or amino derivatives.
• Hydrolysis adds water to esters and amides, with Esters being more susceptible than amides. Aspirin becomes Salicylic + acetic acid.
• Phase II / Conjugation attaches polar molecules (glucuronic acid) to Phase I metabolites.

Glucuronidation

• The most common Phase II pathway, generates highly hydrophilic glucuronides.
• UDP–glucuronosyl transferase enzymes are underdeveloped in neonates, leading to Gray-baby syndrome with Chloramphenicol.
• Cofactor: UDP–Glucuronic acid.

Sulfation

• Requires a phenolic group and uses Sulfotransferase enzymes with PAPS cofactor.

Amino Acid Conjugation

• The first mammalian drug metabolite isolated produced Hippuric Acid product from benzoic acid conjugation.
• Employs N-Acetyl transferase enzyme and Glycine/Glutamine cofactors.

Glutamine Conjugation

• Glutathione (Glu-Cys-Val) scavenges electrophilic drugs with its thiol group, giving "antioxidant property."
• Enzyme: Glutathione-S-transferase, using glutathione cofactor to make mercapturic acid.

Acetyl Conjugation

• Acetylation deactivates N-containing drugs, using NAT enzymes and Acetyl CoA cofactor.

Methyl Conjugation

• Impacts biosynthesis of Epi, Melatonin, catabolism of catecholamine via methyl transferase enzymes and SAM cofactor.

Local Anti-Infectives

• Antiseptics: Used on living tissue
• Disinfectants: Used on inanimate objects

Alcohols and Related Compounds.

• SAR: antibacterial efficacy of primary alcohols (S. aureus) increases to 8C.
• Alcohol USP, aka Spiritus vini rectificatus/Wine Spirit/Grain alcohol, is mostly abused. Alcohol metabolized to Aldehyde by alc dehydrogenase then Acid by Ald dehydrogenase
• Denatured alcohol is unfit for intoxication plus benzene and methanol.
• Rubbing alcohol refrigerates, is astringent, a rubefacient, and mild anesthetic.
• Dehydrated alcohol is 99% ethanol used as chemical reagent.
• Isopropyl alcohol disinfects skin and surgical tools.
• Ethylene oxide is used to sterilize heat-sensitive equipment. It is a gas sterilant via alkylation.
• Formaldehyde contains 37% formaldehyde, plus methanol to retard polymerization, with alkylation MOA.
• Glutaraldehyde is sterilizing solution for equipment that can't be autoclaved.

Phenol and its Derivatives

• Phenol coefficient measures disinfectant potency to kill Salmonella typhi, relative to phenol.
• Phenol (Carbolic Acid) is a protoplasmic poison, but its use is limited.
• Cresol is an inexpensive antiseptic and disinfectant.
• Thymol fights fungal Tinea infections.
• Eugenol is a local anesthetic for toothaches.
• Resorcinol is keratolytic and antiseptic.

Cationic Surfactants

• Benzalkonium Chloride like new Merthiolate, is a detergent and wetting agent, preserved with sodium nitrate.
• Methylbenzethonium Chloride manages diaper rash from Bacterium ammoniagenes.
• Cetylpyridinium Chloride is a general antiseptic approved for Gingivitis.
• Chlorhexidine is used as an irrigation solution and mouthwash.

Dyes

• Gentian Violet (Crystal/Methyl violet) treats yeast infections.
• Some other uses are as Anthelmintic
• Characteristics: Effective at low concentrations, nontoxic, compatible and has a stable shelf life.
• Compounds: Parabens for liquid dosage forms (methyl for mold, propyl for yeasts). Increased molecular weight increases preservative effects.
• Chlorobutanol and Benzyl alcohol have bacteriostatic and preservative effects.
• Benzoic Acid preserves foods/pharmaceuticals at low pH.
• Sorbic acid is an antifungal preservative.

CNS Drugs

Anxiolytic and Sedative Hypnotics

• Barbiturates SAR: A 2,4,6-trioxo hexahydropyrimidine nucleus, alkyl R1 for lipophilicity which causes quick onset/short action.
• Position 5: Alkyl or aromatic groups for sedative-hypnotic action. Two substituents are needed.
• Lipophilicity potency increases the duration of opening via Cl channels.

Benzodiazepines

• Benzodiazepines SAR: N–R at 1 and C=O at 2 are crucial, adding a triazole/imidazole increases potency. Diazepam and Triazolam have triazole fused.
• Ring activity raised by a 2' or 2',6' substitution, Halogens are effective withdrawing groups. Substitution boosts activity.

Antipsychotic Drugs

• General structure and SAR requires a tertiary amine (10; N–R) and withdrawing at (2)
• Halogens improve activity.
• Ring and side chain N must be at least 3C apart for antipsychotic activity.

Antidepressant

• Secondary amines end in "triptyline" EXCEPT Desipramine/Amoxapine.
• Tertiary amines end with "pramine", except Amitriptyline and Doxepin.

Opioid Analgesics’

• Structure: 5 fused rings and a T shape, basic due to tertiary amines.
• Pharmacophore: Phenol ring, aromatic ring & tertiary amine are key for MOA.

Removal of Rings

• Adding methyl at position 3 reduces Morphine activity
• Removing alkene at position 6 increases Morphine activity
• Removing Ring "E" reduces activity
• Removing Ring "D" increases Morphine activity
• Removing Ring "C and D" increases Morphine activity
• Removing Rings B, C, and D retains activity.

Anesthetics - Inhalational

• Require halogenated hydrocarbons for volatility.
• Halothane is a prototype metabolized to trifluoroacetic acid.
• Methoxyflurane is most potent.
• Nitrous Oxide is least potent/safest.

Local Anesthetics

• The structure includes benzene (lipophilic), intermediate chain (ester or amide), and a hydrophilic quaternary amine.

Cholinergic

• Acetylcholine SAR requires a quaternary N, ethylene bridge, and ester. The molecule size cannot be altered nor the methyl group extended.

Adrenergic

• General structure and SAR: features a phenylethylamine and catechol group.
• Substitution impacts activity, with bulkier R1 groups enhancing β-activity, while increasing R2 chain size enhances α-activity.

Adrenergic Antagonist

• Beta-Blockers: Aryloxypropandamines are the chemical class for Beta-Blockers
• Alpha-blockers’ SAR requires a 4-amino group on the quinazoline ring and a heterocyclic moiety on the 2nd position.

H1 Blockers

• Divided into Ethanolamine (most sedating), Ethylenediamine, Piperazine ("-clizine" for motion sickness), and Alkylamine ("-pheniramine").

H2 Antagonist

• Cimetidine is the prototype, with Ranitidine/Famotidine/Nizatidine being derivatives.

Hypoglycemic Agents

• Proton Pump Inhibitors are substituted benzimidazoles, activated by acid.
• Omeprazole is a prototype drug.
• 分为Insulins (Rapid, Short, Intermediate, Long Acting), OHAs: Insulin Secretagogues/Sensitizers/a-Glucosidase & Dipeptidyl Peptidase-4 Inhibitors.
• Sulfonylureas (1st/2nd Gen) act as hypoglycemic agents.
• Biguanides are formed from 2 linked Guanidine molecules.
• Thiazolidinediones and Meglitinides are Insulin Secretagogues.
• Insulins' pharmacokinetic classes include rapid, short, intermediate, and long-acting forms.

Cardiovascular Drugs

Carbonic Anhydrase Inhibitors

• Acetazolamide, a thiadiazole, contains an sulfonamide.
• Mannitol is an Osmotic Diuretic
• Calcium Channel Blockers inhibit contraction and reduce HR.
• Dihydropyridines (DHP) like Nifedipine.
• ACE Inhibitors have “-pril” suffix, like fast-acting Captopril.

Thiazides

• Benzothiadiazines contain a sulfonamide with halogen increasing potency via Hydrogenation
• Loop Diuretics: like Furosemide disrupt kidney function
• K+-Sparing Diuretics: counteract K+ loss from other diuretics like Spironolactone.
• Direct Vasodilators: Hydralazine (NH–NH2), Sodium Nitroprusside, Minoxidil and Diazoxide.
• Antianginals: Nitroglycerin, Isosorbide Dinitrate/Mononitrate, Dipyridamole (w/ ASA), Clopidogrel.

Antiarrhythmics

• Classes per Vaughan Williams classification, focus on action potential stages.
• Amrinone affects contractility. Digoxin helps cardiac glycoside, increasing inotropy (contraction strength), treating HF acutely via IV Dobutamine/Dopamine.

Antibacterial (Chemotherapeutic)

Beta-Lactams: Core is derived from Cys/Val with modifications.

• Penicillins: Inhibit transpeptidase. Natural forms like Penicillin G (Benzylpenicillin) need IM injection.
• cephalosporins: Beta-lactam linked to dihydrothiazine.
• carbapenems: Like Thienamycin, are combined with Cilastatin to prevent nephrotoxicity from metabolism.

Antibacterial (Chemotherapeutic)

• Aminoglycosides: Binds 30s ribosomal subunit in bacteria. Affects

Tetracyclines

• Binds 30s ribosomal subunit in bacteria.
• Macrolides: Contain ester linked ring compounds
• Lincosamides: Contains derivatives and has possible side effects
• Polypeptides: disrupt kidney funtion. Has derivatives
• Unclassified Antibiotics: Prevents protein synthesis. Has derivatives

Azole

• Prevents biosynthesis in bacteria. Has derivatives