This work describes
the synthesis and pharmacological evaluation
of picolinoyl-based peptidomimetics of melanocyte stimulating hormone
release inhibiting factor 1 (MIF-1) as dopamine modulating agents.
Eight novel peptidomimetics were tested for their ability to enhance
the maximal effect of tritiated N-propylapomorphine
([3H]-NPA) at dopamine D2 receptors (D2R). Methyl picolinoyl-l-valyl-l-alaninate (compound 6b) produced a statistically significant increase in the maximal
[3H]-NPA response at 0.01 nM (11.9 ± 3.7%), which
is close to the effect of MIF-1 in this assay at same concentration
(18.3 ± 9.1%). Functional assays measuring cAMP mobilization
in the presence of dopamine corroborate the activity of peptidomimetic 6b as a positive allosteric modulator (PAM) of D2R. In this assay, 6b produced a typical bell-shaped
dose–response curve similar to that of the parent neuropeptide
(18.3 ± 7.1% for 6b vs 15.4 ± 5.5% for MIF-1,
both at 0.1 nM). Dose–response curves for dopamine in the presence
of 6b show EC50 (0.33 ± 0.21 μM
for 6b vs 0.17 ± 0.07 μM for MIF-1) and E
max (86.0 ± 5.4% for 6b vs
93.6 ± 4.4% for MIF-1) comparable to those of MIF-1, both at
0.01 nM. Furthermore, peptidomimetic 6b was tested for
agonist activity at the human D2R and the results show
that it displays no intrinsic agonism effect, endorsing its activity
as a PAM of D2R. Cytotoxic and neurotoxic assays were performed
for peptidomimetic 6b using HEK 293T cells and cortex
neurons from 19 day old Wistar-Kyoto rat embryos, respectively, suggesting
this analogue displays no toxicity effect in these assays up to 100
μM. Conformational energy minimization for 6b shows
that this peptidomimetic cannot adopt the postulated type-II β-turn
bioactive conformation, endorsing the possibility of an extended bioactive
conformation as claimed by other researchers as a second bioactive
conformation of MIF-1. Overall, the pharmacological and toxicological
profile of peptidomimetic 6b together with its favorable
druglike properties and structural simplicity makes it a potential
lead compound for further development and optimization.
An efficient and straightforward orthogonal methodology was successfully developed to achieve constrained l-prolyl-l-leucylglycinamide (PLG) analogues starting from two proline mimetics based on a 2-azanorbornane scaffold. A preliminary dopamine D receptor radiolabeled binding assay with [H]-N-propylnorapomorphine shows that enantiopurity of PLG peptidomimetics based on 2-azanorbornane is a requirement to achieve statistically significant positive modulators of the D receptor. This is the first documented active peptidomimetic of PLG whose bioactivity is not correlated with the C-terminal carboxamide pharmacophore and which cannot adopt the hypothesized type II β-turn conformation.
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