Medicinal Chemistry

5.14 PEPTIDE HORMONES: INTRODUCTION

Peptides are polymers of amino acids. Each amino acid contributes three atoms
(-N(-H)-Cα(-H,-R')-C(=O)-) to the backboneof the peptide. The side-chains of the
individual amino acids then extend outwards from the core backbone. A dipeptideis
composed of two amino acids; a tripeptideis composed of three amino acids; and so
on. An oligopeptideis composed of a small number of amino acids; a protein is com-
posed of a larger number of amino acids. Most peptide hormones are oligopeptides.
Except for glycine, each of the twenty naturally occurring amino acids contributes
chiralityto the peptide by having stereogenic centersat each Cαatom. This enables
stereospecific interactions between the peptide hormone and its receptor. This latter
feature is invaluable in drug design since it permits analogs of peptide hormones to be
designed with the capability of a unique stereospecific interaction with their receptors.

5.15 PEPTIDE HORMONES OF THE BRAIN

Although it is the dominant organ of the neural system, the brain also has an endocrine
function, enabling the all-important overlap between neural and endocrine control
systems. The most obvious and classically recognized hormonal function of the brain
arises from the peptide hormones of the hypothalamus. The hypothalamus is intimately
connected with the pituitary, producing the hypothalamic–pituitary axis. The hypothal-
amus is part of the brain; the pituitary, although located within the skull, is not part of
the brain but is part of the endocrine system. Peptide hormones from the hypothalamus
influence pituitary function and thus endocrine function throughout the body.
In addition to these classical hypothalamic peptide hormones, the brain also produces
a number of other peptides that can be considered as peptide hormones. These peptides,
or neuropeptides, are functionally difficult to categorize and have properties of neuro-
transmitters, neurohormones, and neuromodulators. One given peptide can exhibit one
or more of these properties, depending upon its location in the nervous system. A neuro-
peptide may diffuse to an adjacent neuron to elicit a response, thus acting as a neuro-
transmitter; conversely, the same neuropeptide may also be transported to cells that are
further away by the bloodstream before eliciting a response, thus acting as a hormone.
These “multi-tasking” neuropeptides are found in the central nervous system, periph-
eral nervous system, and gastrointestinal tract.
The functions of CNS neuropeptide neurohormones seem to be multiple, because the
possible variations and fine-tuning of signals offer nearly inexhaustible possibilities
that may even satisfy the requirements of the enormous complexity of the homeostatic
integration and control of feeding, temperature regulation, circulation, pain, learning,
and many other behavioral and developmental challenges that continuously confront
organisms. Our modest initial recognition of the immense complexity of neuro-
endocrine functions, combined with our rudimentary understanding of ion channel
function, raises the hope that therein lies the key to future understanding of higher
mental functions such as learning and memory.

5.15.1 Peptide Hormones of the Brain: Non-Hypothalamic

Since the mid-1970s, a major revolution has occurred in our understanding of neuro-
transmission and endocrinology, combining these two previously distinct disciplines

338 MEDICINAL CHEMISTRY