Inositol triphosphate is water soluble and therefore diffuses into the cytoplasm, where
it mobilizes calcium from its stores in microsomes or the endoplasmic reticulum. The
Ca^2 +ions then activate Ca-dependent kinases (like troponin C in muscle) directly or bind
to the ubiquitous Ca-binding protein calmodulin, which activates calmodulin-dependent
kinases. These kinases, in turn, phosphorylate cell-specific enzymes.
Diacylglycerol, on the other hand, is lipid soluble and remains in the lipid bilayer of
the membrane. There it can activate protein kinase C (PKC), a very important and widely
distributed enzyme which serves many systems through phosphorylation, including
neurotransmitters (acetylcholine,α 1 - and β-adrenoceptors, serotonin), peptide hormones
(insulin, epidermal growth hormone, somatomedin), and various cellular functions
(glycogen metabolism, muscle activity, structural proteins, etc.), and also interacts with
guanylate cyclase. In addition to diacylglycerol, another normal membrane lipid, phos-
phatidylserine, is needed for activation of PKC. The DG–IP 3 limbs of the pathway
usually proceed simultaneously.
The phosphatidylinositol pathway is completed by regeneration of the phospholipid
from IP 3 and DG. It is remarkable that IP 3 is successively dephosphorylated to mositol.
The last step of this sequence is inhibited by Li+ions, which block phosphatidylinosi-
tol synthesis. Li salts are used to control the symptoms of manic-depressive illness, an
affective mental disorder (see section 3.5.4), and it is thus tempting to implicate the last
reaction of the PI pathway in the etiology of this disorder.
2.11 SELECTING A RECEPTOR APPROPRIATE
FOR DRUG DESIGN
In developing new chemical entities as therapeutics, the medicinal chemist or drug
designer is confronted with the task of identifying and selecting a receptor against
which to target the drug to be designed; this is not a trivial task. Philosophically, there
are many basic approaches to receptor site selection that may be pursued when tackling
this task.
96 MEDICINAL CHEMISTRY
Figure 2.5 Generalized model of the G-protein coupled receptor.