2 research outputs found
Synthesis of Gly-ψ[(<i>Z</i>)CFCH]-Phe, a Fluoroalkene Dipeptide Isostere, and Its Incorporation into a Leu-enkephalin Peptidomimetic
A new
Leu-enkephalin peptidomimetic designed to explore the hydrogen
bond acceptor ability of the third peptide bond has been prepared
and studied. This new analog is produced by replacing the third amide
of Leu-enkephalin with a fluoroalkene. An efficient and innovative
synthesis of the corresponding dipeptide surrogate Fmoc-Gly-ψ[(<i>Z</i>)CFCH]-Phe-OH is described. The key step involves
the alkylation of a tin dienolate from the less hindered face of its
chiral sulfonamide auxiliary derived from camphor. Once its synthesis
was complete, its incorporation into the peptidomimetic sequence was
achieved on a solid support with chlorotrityl resin following the
Fmoc strategy. The peptidomimetic was characterized using competition
binding with [<sup>125</sup>I]-deltorphin I on membrane extracts of
HEK293 cells expressing the mouse delta opioid receptor (DOPr) and
based on its abilities to inhibit the electrically induced contractions
of the mouse <i>vas deferens</i> and to activate the ERK1/2
signaling pathway in DRGF11/DOPr-GFP cells. Together with our previous
observations, our findings strongly suggest that the third amide bond
of Leu-enkephalin primarily acts as a hydrogen bond acceptor in DOPr.
Consequently, this amide bond can be successfully replaced by an ester,
a thioamide, or a fluoroalkene without greatly impacting the binding
or biological activity of the corresponding analogs. The lipophilicity
(LogD<sub>7.4</sub>) of the active analog was also measured. It appears
that fluoroalkenes are almost as efficient at increasing the lipophilicity
as normal alkenes
Synthesis and Evaluation of a <sup>64</sup>Cu-Conjugate, a Selective δ‑Opioid Receptor Positron Emission Tomography Imaging Agent
Given the putative
selectivity of the antagonist TIPP (Tyr-Tic-Phe-Phe)
for δ-opioid receptors (DOP), this compound was selected for
the design of a novel <sup>64</sup>Cu-radiolabeled potent and selective
DOP positron emission tomography (PET) imaging agent. <i>Ex vivo</i> autoradiography of TIPPD-PEG-K(NOTA/<sup>64</sup>Cu)-NH<sub>2</sub> on rat brain sections produced a distribution pattern consistent
with the known expression of DOP. Taken together, the <i>in vitro</i> and <i>ex vivo</i> data indicate that this <sup>64</sup>Cu-tracer holds promise for studying the DOP by means of PET