New Serotonin 5‑HT<sub>1A</sub> Receptor Agonists
Endowed with Antinociceptive Activity <i>in Vivo</i>
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Abstract
We
report the synthesis of new compounds <b>4–35</b> based
on two different openings (A and B) of the chromane
ring present in the previously identified 5-HT<sub>1A</sub> receptor
(5-HT<sub>1A</sub>R) ligand <b>3</b>. The synthesized compounds
were assessed for binding affinity, selectivity, and functional activity
at the 5-HT<sub>1A</sub>R. Selected candidates resulting from B opening
were also evaluated for their potential antinociceptive effect <i>in vivo</i> and pharmacokinetic properties <i>in vitro</i>. Analogue <b>19</b> [2-(4-{[2-(2-ethoxyphenoxy)ethyl]amino}butyl)tetrahydro-1<i>H</i>-pyrrolo[1,2-<i>c</i>]imidazole-1,3(2<i>H</i>)-dione] has been characterized as a high-affinity and
potent 5-HT<sub>1A</sub>R agonist (<i>K</i><sub>i</sub> =
2.3 nM; EC<sub>50</sub> = 19 nM). Pharmacokinetic studies indicated
that compound <b>19</b> displays a good metabolic stability
in human liver microsomes (<i>t</i><sub>1/2</sub> ∼
3 h and CL<sub>int</sub> = 3.5 mL/min/kg, at 5 μM), and a low
level of protein binding (25%, at 5 μM). Interestingly, <b>19</b> (3 mg/kg, ip, and 30 mg/kg, po) caused
significant attenuation of formalin-induced behavior in early and
late phases of the mouse intradermal formalin test
of pain, and this <i>in vivo</i> effect was reversed by
the selective 5-HT<sub>1A</sub>R antagonist WAY-100635. Thus, the
new 5-HT<sub>1A</sub>R agonist identified in this work, <b>19</b>, exhibits oral analgesic activity, and the results herein represent
a step toward identifying new therapeutics for the control of pain
