ZJ 43

IC50: 2.4 nM

ZJ-43 is a N-acetylaspartylglutamate (NAAG) peptidase inhibitor.

The peptide neurotransmitter N-acetylaspartylglutamate (NAAG) is reported to act as an agonist at group II metabotropic glutamate receptors. NAAG is inactivated by extracellular peptidase activity leading to yielding glutamate and N-acetylaspartate.

In vitro: As a potent inhibitor of glutamate carboxypeptidase II and III (GCP II and III) with Kivalues of 0.8 and 23 nM respectively, ZJ-43 inhibited the hydrolysis of NAAG via indirect interactions with NMDA or metabotropic glutamate receptors [1].

In vivo: Intravenous injection of ZJ-43 coiuld suppress both phases of the agitation behaviour induced by paw formalin injection in the rat neuropathic pain model. Moreover, intravenous administration of ZJ-43 attenuated the level of mechanical allodynia induced by the nerve ligation. These effects of ZJ-43 in both the formalin test and the partial sciatic nerve ligation model were completely antagonized by pretreatment with LY-341495, which was a highly selective group II mGluR antagonist [1].

Clinical trial: N/A

Reference:
[1] Yamamoto T1,Hirasawa S,Wroblewska B,Grajkowska E,Zhou J,Kozikowski A,Wroblewski J,Neale JH.  Antinociceptive effects of N-acetylaspartylglutamate (NAAG) peptidase inhibitors ZJ-11, ZJ-17 and ZJ-43 in the rat formalin test and in the rat neuropathic pain model. Eur J Neurosci.2004 Jul;20(2):483-94.

Antinociceptive effects of N-acetylaspartylglutamate (NAAG) peptidase inhibitors ZJ-11, ZJ-17 and ZJ-43 in the rat formalin test and in the rat neuropathic pain model.[Pubmed:15233757]

Eur J Neurosci. 2004 Jul;20(2):483-94.

The peptide neurotransmitter N-acetylaspartylglutamate (NAAG) acts as an agonist at group II metabotropic glutamate receptors (mGluRs). NAAG is inactivated by extracellular peptidase activity yielding glutamate and N-acetylaspartate. We recently developed a series of potent NAAG peptidase inhibitors, including ZJ-11, ZJ-17 and ZJ-43. In the present study, we examined the effects of intrathecally administered ZJ-11 and ZJ-17 and intravenously administered ZJ-11 and ZJ-43 in the rat formalin test (an inflammatory pain model) and in the rat partial sciatic nerve ligation model (a neuropathic pain model). Intrathecal injection of ZJ-11 or ZJ-17 or intravenous injection of ZJ-11 or ZJ-43 suppressed both phases of the agitation behaviour induced by paw formalin injection. Intrathecal and intravenous injection of ZJ-11 suppressed the expression of Fos-like immunoreactivity, induced by paw formalin injection, in laminae I-II in segments L4-L5 of the spinal cord, suggesting an action on sensory spinal transmission. Partial sciatic nerve ligation induced significant mechanical allodynia 7 days after the nerve injury. Intrathecal injection of ZJ-11 or ZJ-17 or intravenous administration of ZJ-11 or ZJ-43 attenuated the level of mechanical allodynia induced by this nerve ligation. These effects of intrathecally or intravenously administered ZJ compounds in both the formalin test and the partial sciatic nerve ligation model were completely antagonized by pretreatment with LY-341495, a highly selective group II mGluR antagonist. Thus, elevation of extracellular NAAG, induced by the inhibition of NAAG peptidase, activates group II mGluRs and produces an analgesic effect in neuropathic and inflammatory and pain models. In contrast, peptidase inhibition did not affect the threshold for withdrawal from a noxious mechanical stimulus or from an acute thermal stimulus in the hotplate test.