Throughout the 1990s, molecular cloning enabled the identification of at least three
novel galanin receptors: GALR1–3. These receptors operate via G-protein effectors.
Work on developing nonpeptidic small-molecule antagonists for these receptors is
currently under way. This design work is being greatly facilitated by a combination of
experimental and molecular modeling methodologies. The conformation of the galanin
peptide has been modeled using^1 H-NMR spectroscopic techniques; a three-dimensional
model of the GALR1 receptor has been deduced from molecular modeling studies based
on the transmembrane helices of the bacteriorhodopsin protein. These diverse structural
studies may permit the development of antagonists which may be useful in the treatment
of obesity, dementia-associated cognitive decline, and peripheral nerve injury.
4.10.4 NeurokininsNeurokinins (or tachykinins) constitute a family of neuropeptides that includes substance
P (SP), neurokinin A (NKA) and neurokinin B (NKB). Neurokinins are widely distributed
throughout the central and peripheral nervous systems. The first neurokinin to receive
extensive study was substance P. Substance P (for “powder”), an undecapeptide of the
sequence Arg–Pro–Lys–Pro–Gln–Gln–Phe–Phe–Gly–Leu–Met–NH 2 , is an extremely
active excitatory peptide neurotransmitter. The mechanisms of its biosynthesis and inacti-
vation remain incompletely elucidated. Nonetheless, the localized neuronal presence of SP
and its release in the salivary gland and in several brain regions suggest that it has a neu-
rotransmitter or neurohormonal role. Its coexistence in some serotonergic and histaminer-
gic neurons in the CNS is an interesting phenomenon. Substance P may be involved in pain
mediation, as suggested by the fact that its injection into the brain has produced analgesia
and it may regulate catecholamine turnover. SP is involved in mediating pain responses
peripherally as well as centrally. Small fibers of the peripheral pain-sensitive neurons use
SP as excitatory transmitter, and neurotransmitter release is inhibited by opiates at the
dorsal horn of the spinal cord. In the CNS, the effect of SP is inhibitory, analgesic, and is
stimulated by the endogenous opiate neuropeptide met-enkephalin. In stressed animals, SP
can block the analgesic effect of endogenous opiates. The peripheral sensory effects of
SP are mediated by the C-terminal fragment (6–8 amino acids) of SP, whereas the central
analgesic effects are due to the N-terminal fragment, which also stimulates learning and
memory. Thus post-translational peptide-modifying enzymes may decide which effect will
prevail, in addition to the receptors at the site of action.
Over the past decade, considerable effort has been expended on the design and syn-
thesis of nonpeptidic antagonists for the three receptors (NK1–3) to which SP, NKA,
and NKB bind. These antagonists could have therapeutic use in conditions such as
migraine, arthritis, inflammatory diseases such as cystitis, psoriasis, asthma, anxiety,
depression, and emesis (vomiting). A variety of NK1–3 receptor antagonists have been
designed and synthesized. The majority of these compounds are polyheterocyclics.
4.11 SMALL-MOLECULE NEUROTRANSMITTERS:
GASES (NITRIC OXIDE, CARBON MONOXIDE)
Peptide neurotransmitters present problems for the drug designer because they are too
large. Gaseous neurotransmitters likewise present problems for the drug designer, but
NEUROTRANSMITTERS AND THEIR RECEPTORS 291