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J Pharmacol Ther Res 2017 Volume 1 Issue 2
allied
academies
November 02-03, 2017 Chicago, USA
4
th
International Congress on
International Conference and Exhibition on
Drug Discovery, Designing and Development
Biochemistry, Molecular Biology: R&D
&
S
omatostatin (SST) occurs in two biologically active forms
SST-14 and a N-terminally-extended form SST-28. SST
exerts its effects by binding to a family of G protein-coupled
receptors designated sst1-sst5. Structure-activity studies
have shown that the tetrapeptide fragment, Phe7-Trp8-
Lys9-Thr10, comprises the critical β-turn of SST. Although
Phe7 and Thr10 can be modified, Trp8 and Lys9 are essential
for biological activity. Since nonpeptide SST ligands offer
therapeutic advantages over peptides, a screening program
was initiated to identify a nonpeptide SST ligand with affinity
for sst1-sst5. The search focused on the following: An
aromatic moiety to mimic Phe7; a heteroaromatic nucleus
to mimic Trp8, and a primary amine or other basic group to
mimic Lys9. Using these search criteria, NNC 26-9100 was
identified as the first sst4 agonist having high affinity (Ki=6
nM) and 100-fold sst4/sst2 selectivity at cloned human sst4
receptors. In a forskolin-induced cAMP assay, NNC 26-9100
potently inhibited cAMP accumulation and was shown to be
a full agonist. NNC 26-9100 increased the expression of the
enzyme neprilysin in the SAMP8 mouse model of Alzheimer’s
disease. Neprilysin is the major Aβ-42 peptide degrading
enzyme in the brain. Our studies demonstrate that NNC
26-9100 reduces Aβ-42 peptide levels in mouse cortex and
that this reduction is associated with increased expression of
neprilysin. Acute and chronic administration of NNC 26-9100
also increased learning and memory in SAMP8 mice using
the T-maze test. These results suggest that NNC 26-9100 is a
disease-modifying agent with potential use in the treatment
of Alzheimer’s disease. Current studies in our laboratory are
focused on the discovery on novel heterocyclic scaffolds with
high affinity and selectivity at sst4 receptors.
Speaker Biography
Michael Crider is Professor and Chair of the Department of Pharmaceutical Sciences at
the School of Pharmacy at Southern Illinois University Edwardsville. Prior to assuming
his present position, he held faculty positions at the University of Toledo and the
University of Louisiana at Monroe. He has directed the research of 19 MS and PhD
students. The focus of his research is in the design and synthesis of anticonvulsants,
dopaminergics, and nonpeptide somatostatin agonists.
e:
mcrider@siue.eduMichael Crider
Southern Illinois University Edwardsville, USA
Development of Somatostatin Subtype 4 (SST4) agonists for potential use in
Alzheimer’s disease