MEDICINAL CHEMISTRY

on positions A 8 and A 10, are alanine and valine). Thus, there is nearly a complete
homology between human insulin and porcine insulin in the amino acid sequence.
The natural sources of insulin are mainly porcine and bovine pancreatic tissues. In
comparison to synthetic insulin, natural is cheaper and is readily obtained in large
amounts. SAR studies carried out on insulin revealed the following points :
(1)There exist a definite relationship between the conformation of insulin molecule and
its activity. Any attempt to change this conformation leads to decrease in activity.
(2)Disturbance in the sequence of amino acids in chain A reduces the activity while
amino acids from one to six and 28 to 30 can be removed from chain B, without
significantly affecting the activity.
(3)Reduction of either chains, abolishes the activity.
(4)Any modification of the side-chain carboxyl groups or the tyrosine residues tend to
decrease the activity.
It may be concluded that chemical modifications in the insulin structure fail to potentiate
the hormone activity. Some analogs have been prepared but are of limited use to study
insulin receptors.
The therapeutic importance of zinc and chromium in the treatment of diabetes is recently
reviewed. Zinc, being an integral part of the insulin structure, is also found to affect
carbohydrate metabolism while chromium activates insulin at its receptor sites and is
found to increase both, the affinity and intrinsic activity of insulin.
Mechanism of Action
(i)Cyclic-AMP plays an important role in phosphorylation of various protein kinase
involved in the metabolism of carbohydrate, proteins and fat. Various hormones affect
the blood glucose level by influencing the concentration of c-AMP. For example,
hormones like epinephrine, glucagon and ACTH tend to increase intracellular c-AMP
concentration. Similar effects are also exerted by secretin, thyroxine and TSH, While
insulin, melatonin, PGF2 tend to lower down intracellular c-AMP concentration. Thus
insulin promotes dephosphorylation of activated protein kinases.
(ii)Triglyceride lipase is involved in lipolysis insulin process. It is activated by c-AMP
through phosphorylation. Insulin exerts antilipolytic effect by catalysing
dephosphorylation process. Similarly by dephosphorylation of pyruvate dehydrogenase,
the conversion of pyruvate to glucose is inhibited by insulin. Hence pyruvate has to get
converted to fat.
(2) Oral Hypoglycemic agents
a)Guanidine derivatives: e.g. Phenformin, Metformin, other biguanides
Biguanides
The parent lead compound of this series, guanidine was reported to lower blood glucose
levels in animals in 1918. High toxicities associated with its use necessitated the search