W7 Insulin Chem and Antidiabetics (MM) Flashcards
Structure of Insulin:
Name of insulin derived from beef or pork?
- The first hormone to be isolated (more than
100 years ago) - Molecular structure (of one monomer):
C257H383N65O77S6 (dont memorise) - It is a dimer (two peptide chains)
- A-Chain: 21 Amino Acids
- B-Chain: 30 Amino Acids
- Linker: 35 Amino Acids
- Disulfide Bonds: 2 which link A and B-chains
- Bovine Insulin: 3 differences in AA sequence
- Porcine Insulin: Only 1 AA difference
- Produced and stored as a hexamer but the
active form is the monomer
What is a Disulfide Bond / Disulfide Bridge?
- Usually formed by the coupling of
two thiol groups - Therefore, often seen between
two cysteine residues in peptides/ proteins - Synthesis in the lab often requires iodine in the presence of base
- Weaker than C-C and C-H bonds
- Longer than C-C bonds (2.05 Å)
What are the 2 types of Insulin sensitisers?
- Biguanides (Metformin)
- Thiazolidinediones (Pioglitazone)
Features of Biguanides?
- Comprised of 2 guanidine groups
- Polar and hydrophilic
- Complete synthesis of Metformin
Features of Guanidine?
- Nitrogen rich
- Organic compound
- Found in nature (turnip juice, mussels,
earthworms) - Exists in ambient conditions
- Similar to carbonic acid (but carbonic acid
does not exist in ambient conditions)
Insulin Sensitisers: Biguanides
What are the 3 steps in the synthesis of Metformin?
- Dimethylamine hydrochloride is depronated by cyanoguanidine
- Nucleophilic attack of the cyanoguanidine by the lone pair of the dimethylamine nitrogen
- Proton transfer yields the final product (metformin HCl salt)
Insulin Sensitisers:
Features of Thiazolidinediones?
Example?
- All contain 5-membered C3NS heterocycle
- Pioglitazone is only TZD drug approved for use in UK
- Rosiglitazone is used in the US and other markets but banned in Europe due to risk of heart attack
Insulin Secretagogues:
What is their function?
What are examples? (4)
Increase insulin secretion from the pancreas
- Sulfonylureas
- Meglitinides
- Incretin Mimetics
- Gliptins
Insulin Secretagogues
General structure of Sulfonylureas?
- sulfonyl group (-S(=O)2)
- ureylene group (NHONH)
- Substituent at the para position
- Terminal group attached at urea N
Note the difference between 1st generation
and 2nd generation sulfonylurea drugs
1st gen:
* Simpler, containing aromatic rings and short side chains
2nd gen:
* More potent, higher receptor affinity
* Longer duration of action
* Amide/ Carboxamide group in 2nd gen, branched alkyl or heterocyclic substituents
Insulin Secretagogues: Meglitinides
What are they?
Examples?
- Meglitinides are benzamides with hypoglycemic activity
- Benzamide is an organic compound with the chemical formula C7H7NO
- Most simple derivative of benzoic acid
- Benzamides make up a huge number of commercial drugs (analgesics,antidepressants, antiemetics, antipsychotics, opiods)
- Repaglinide is the secretagogue used
in the UK
Benzamide, Benzoic acid, Salicylamide (analgesic) Moclobemide (antidepressant) Metoclopramide (antiemetic)
Insulin Secretagogues: Incretin Mimetics
What is their function?
- Also known as Glucagon-like Peptide 1 (GLP-1) receptor agonists
- Mimic incretin hormones* (such as GLP-1)
- Injectable drugs
- Most well-known: Semaglutide
*Group of hormones that are released in upper GI after eating to stimulate pancreas to release insulin
Insulin Secretagogues: Gliptins
MOA?
Examples
- Also known as DPP-4 Inhibitors
- Work by inhibiting dipeptidyl-peptidase-4
- DPP-4 inactivates incretin hormones
- Structures are quite varied (and too complex to study in detail)
Sitagliptin, Saxagliptin, Linagliptin, Anagliptin
Miscellaneous: Gliflozins
Gliflozins share a common general structure:
* Glucose sugar
* Aromatic group at β-position at anomeric carbon
* Aromatic group forms part of a diarylmethylene structure
Miscellaneous: Acarbose
MOA?
- Mimics polysaccharides to block the α-glucosidase from breaking them down into glucose
- Therefore, has a pseudo-tetrasaccharide structure
