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Discovery of Potent Antiallodynic Agents for Neuropathic Pain Targeting P2X3 Receptors.
Jung YH
,
Kim YO
,
Lin H
,
Cho JH
,
Park JH
,
Lee SD
,
Bae J
,
Kang KM
,
Kim YG
,
Pae AN
,
Ko H
,
Park CS
,
Yoon MH
,
Kim YC
.
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Antagonism of the P2X3 receptor is one of the potential therapeutic strategies for the management of neuropathic pain because P2X3 receptors are predominantly localized on small to medium diameter C- and Aδ-fiber primary afferent neurons, which are related to the pain-sensing system. In this study, 5-hydroxy pyridine derivatives were designed, synthesized, and evaluated for their in vitro biological activities by two-electrode voltage clamp assay at hP2X3 receptors. Among the novel hP2X3 receptor antagonists, intrathecal treatment of compound 29 showed parallel efficacy with pregabalin (calcium channel modulator) and higher efficacy than AF353 (P2X3 receptor antagonist) in the evaluation of its antiallodynic effects in spinal nerve ligation rats. However, because compound 29 was inactive by intraperitoneal administration in neuropathic pain animal models due to low cell permeability, the corresponding methyl ester analogue, 28, which could be converted to compound 29 in vivo, was investigated as a prodrug concept. Intravenous injection of compound 28 resulted in potent antiallodynic effects, with ED 50 values of 2.62 and 2.93 mg/kg in spinal nerve ligation and chemotherapy-induced peripheral neuropathy rats, respectively, indicating that new drug development targeting the P2X3 receptor could be promising for neuropathic pain, a disease with high unmet medical needs.
Scheme 1. Synthesis of 3,4-Dicarboxypyridine Derivativesa
Scheme 2. Synthesis of 5-Hydroxypyridine Derivatives a
Scheme 3. Synthesis of 5-Hydroxypyridine Derivatives a
Scheme 4. Synthesis of 5-Hydroxypyridine Derivatives a
Figure 2. Antiallodynic effects of SNL rats by intrathecal administration of pregabalin, AF353 and compound 29. The withdrawal threshold or the percentage of maximal possible effect (% MPE at 1 μg) represents the mean ± SEM of 5–6 rats for each experimental group. The antiallodynic efficacies of pregabalin (65 ± 9%), AF353 (32 ± 11%), and compound 29 (58 ± 19%) were observed in SNL rats. Compared with vehicle, *P < 0.05.
Figure 3. Antiallodynic effects of SNL rats by intravenous administration of compound 28. The withdrawal threshold or the percentage of maximal possible effect (% MPE) represents the mean ± SEM of 5–6 rats for each experimental group. The antiallodynic efficacy of compound 28 (ED50 values of 2.62 mg/kg) was observed in SNL rats. Compared with vehicle, **P < 0.01, ***P < 0.001.
Figure 4. Antiallodynic effects of CIPN rats by intravenous administration of compound 28. The withdrawal threshold or the percentage of maximal possible effect (% MPE) represents the mean ± SEM of 5–6 rats for each experimental group. The antiallodynic efficacy of compound 28 (ED50 values of 2.93 mg/kg) was observed in CIPN rats. Compared with vehicle, ***P < 0.001.
Figure 5. Antiallodynic effects of SNL rats by intrathecal (A,B) or oral (C,D) administration of compound 28. The withdrawal threshold or the percentage of maximal possible effect (% MPE) represents the mean ± SEM of 5–6 rats for each experimental group. Intrathecal or oral administration of compound 28 did not show any antiallodynic effects.
