Medicinal Chemistry

innervationand is controlled by a complex array of neurons, making it an ideal target
for neuroactive agents.)

4.10.2 Neuropeptide Y

Neuropeptide Y (NPY) is another messenger molecule that demonstrates the close
interplay between the nervous and gastrointestinal systems. Neuropeptide Y, a member
of the pancreatic polypeptide family, is a 36-amino-acid neuropeptide that is widely
distributed in both the central and peripheral nervous systems. NPY elicits its physio-
logical effects via interaction with at least six different G-protein-coupled receptors
(Y1–Y6), all of which demonstrate varying anatomical distributions: Y1 (vascular
smooth muscle of blood vessels and brain); Y2 (peripheral nervous system and several
brain regions); Y3 (heart, colon, adrenals, brainstem); Y4 (small intestine, pancreas); Y5
(brain, testis, spleen); and Y6 (hypothalamus, kidney). Arising from this plethora of
receptors throughout the body, NPY plays central roles in multiple conditions: obesity
(via Y1 and Y5); anxiety (via Y1); heart rate and blood pressure (via Y3); and ethanol
abuse. Molecular modeling-assisted rational drug design has been used to develop
antagonists to many of these receptor subtypes.

4.10.2.1 Neuropeptides and Obesity

Neuropeptides such as NPY may represent novel approaches to the treatment of obesity.
Obesity is a disorder of epidemic proportions in developed countries, especially North
America. To make matters worse, obesity spawns a host of other health problems: dia-
betes, high blood pressure, osteoarthritis, heart attack, and stroke. It is easy to say that the
solution is simple (“eat less”); in reality, this is not happening, and the general public is
inundated with a library of self-help diet books and a litany of drastic (and sometimes
dangerous) diets. An appetite suppressant pill is a superficial fix that fails to address the
complexities of obesity, hence the high rate of failure. Arguably, there may be a need for
two separate diet pills: one that helps take weight off and one that helps to keep weight
off (many people find it “easy to lose the weight and even easier to put it back on”). These
two processes may be biochemically distinct, affording separate targets for drug design.
While the gratification that comes from eating may seem to be centered in the upper
abdomen, in reality it comes from the brain. Neuropeptides, such as NPY, may offer novel
approaches to the pharmacological management of this ever-growing problem.

4.10.3 Galanin

Galanin is a neuropeptide with widespread distribution in both the central and peripheral
nervous systems. Human galanin (4.226) is a 30-amino-acid peptide that inhibits the
release of other neurotransmitters and in doing so plays a role in memory acquisition,
sexual behaviour modulation, gastrointestinal mobility, and the appreciation of pain.

290 MEDICINAL CHEMISTRY

Galanin

(4.226)