Medicinal Chemistry

because they are too small. It is not feasible to synthesize analogs of a substance like
NO—it only has two atoms. Rather, it becomes necessary to appreciate the metabolism
of the neurotransmitter and to endeavor to modify the activities of enzymes and other
cofactors. Given the emerging importance of NO, this activity is under serious pursuit
by many academic and industrial groups. A growing body of literature also supports the
observation that carbon monoxide may also be a gaseous neurotransmitter. Together,
NO and CO are recognized as unconventional neurotransmitters.

4.11.1 Discovery of NO as a Messenger Substance

Nitric oxide was first reported by Joseph Priestly (the discoverer of oxygen) in 1790.
Until fairly recently, nitric oxide (NO) was considered primarily for its role as a toxic
smog pollutant. As a chemical substance, it was only of interest to inorganic and
organometallic chemists. However, by the early 1990s it was realized that NO was also
a truly unique messenger molecule involved in a wide range of physiological processes.
Perhaps most importantly, NO was recognized as a neurotransmitter within the central
nervous system—an amazing observation given the simplicity of the molecule. In
recognition of this significance, the editors of the research journal Sciencedubbed NO
with the honour “Molecule of the Year” in 1992.
The discovery of NO as a messenger occurred over a fairly brief timespan—less than
10 years. In 1980, Furchgott and Zawadzki, while studying isolated smooth muscle prepa-
rations, discovered that, following stimulation with acetylcholine, a short-lived vasodilat-
ing substance was released into blood vessels. They called this substance endothelium
derived relaxing factor (EDRF). In 1987, three independent research groups reported
that EDRF and NO were one and the same molecule. Subsequent research revealed that
NO was generated by many cells throughout the body and was even a neurotransmitter
in the CNS. The 1998 Nobel Prize for Physiology and Medicine was bestowed upon
Furchgott, Ignarro, and Murad for their pioneering contributions to the identification
and elaboration of NO as a messenger substance.

4.11.2 Metabolism of NO

The synthesis of NO requires merely one step: the conversion of L-arginine into NO
and citrulline. This conversion is catalyzed by the nitric oxide synthase (NOS) enzyme.
Three distinct isoforms of the NOS enzyme have been cloned: Isoform I (nNOS; chro-
mosome 12) is a Ca^2 +-dependent neuronal form of the enzyme; Isoform II (mNOS or
iNOS; chromosome 17) is a Ca^2 +-independent macrophage inducible form of the
enzyme found in microglia; Isoform III (eNOS, chromosome 7) is a Ca^2 +-dependent
form found in the endothelial cells that line blood vessels. Since NO is an extremely
important messenger substance, the NOS enzyme is exquisitely regulated by processes
such as phosphorylation and hormonal control.
Once synthesized, NO behaves somewhat differently from classical neurotrans-
mitters. NO is not released from neurons in a Ca^2 +-dependent exocytotic process;
rather, it diffuses freely out of the neuron and to the next neuron. Once it reaches its
target enzyme, NO does not interact with specific membrane-associated receptor pro-
teins; instead, it interacts with second-messenger molecules in the receiving neuron

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