approach using antiglutamatergic therapies. The rodent model of stroke does not fully
capture these complexities in a realistic manner.
In addition to failed trials with antiglutamatergic neuroprotectants, other approaches to
neuroprotectant design for stroke have likewise failed: antagonism of voltage-gated Ca^2 +
channels, antagonism of voltage-gated Na+channels, inhibition of nitric oxide synthase,
and scavenging of free radicals. Several recent high-profile failures in designing therapies
for stroke suggest that a deeper understanding of stroke as a biological and pathological
phenomenon may be required as a prerequisite to the improved design of stroke therapies.
4.10 LARGE-MOLECULE NEUROTRANSMITTERS: PEPTIDES
Although the majority of neurotransmitters are relatively small molecules, there is also
a variety of neurotransmitters that are peptides. Peptide neurotransmitters present
unique challenges for the drug designer. Whereas the design of agonists and competi-
tive antagonists for small-molecule neurotransmitters (e.g., glutamate) may be concep-
tually straightforward, the same is not the case with peptidic neurotransmitters.
Designing a small molecule to either mimic or block a peptide is a nontrivial task. The
peptide neurotransmitter is a large, floppy molecule, which may interact with a recep-
tor via many points of contact. Determining the bioactive conformation of a peptide is
difficult; as described in chapter 1, computational drug design around peptides is hin-
dered by a multiple minima problem. As described in chapter 3, peptidomimetic chem-
istry describes an approach to producing small-molecule drugs based on larger
peptides. Regardless of these design challenges, a number of important peptide neuro-
transmitters are being actively studied in the search for new therapeutics. Currently,
more than 20 peptide neurotransmitters that could be useful platforms for drug design
have been identified (see table 4.3). Although all of these are interesting, we will only
discuss several representative examples.
4.10.1 Corticotropin Releasing FactorCorticotropin releasing factor (CRF) is a neuropeptide that falls into the broad spectrum
of having neurotransmitter/neurohormonal/neuromodulator activities. CRF prepares the
host organism for response to a variety of stressors including impending physical trauma,
insults to the endocrine or immune systems, and difficult social interactions. In the CNS,
CRF influences neurons located in higher cortical centers. Not surprisingly, hyper- or
hypo-activity of the CRF system can participate in the mechanisms of a variety of human
disorders: depression, stress-induced gastrointestinal disorders, drug addiction, pain, and
eating disorders. The CRF system has also been implicated in Alzheimer’s disease
and Parkinson’s disease. CRF exerts its actions through one of two different types of
G-protein-coupled receptors (CRF-1, CRF-2), each being encoded by separate genes.
Distinct subtypes of these two receptors (CRF-1α, CRF-1β, CRF-1γ, CRF-1σ; CRF-2α,
CRF-2β, CRF-2γ) arise from different sequence modifications and differ in their
anatomical location and in their responsiveness to various exogenous ligands.
The design and synthesis of low molecular weight nonpeptide ligands for the CRF
receptors has been, and continues to be, a very active area of research. The design of
CRF-1 antagonists has been more successful than that of CRF-2 agents; this design
process has been greatly facilitated by molecular modeling and quantum pharmacology
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