• 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • br Concluding remarks Several orphan GPCRs


    Concluding remarks Several orphan GPCRs have expression profiles that indicate they are worthy of consideration as therapeutic targets. This view can be supported via various transgenic techniques, and it would be interesting to have wide-ranging phenotypic information on GPR35 knockout mice. Based on the number of GPR35 active compounds identified recently in very small-scale screens 12, 23, 33, there is reason to hope that more extensive screens, along with follow-up medical chemistry programmes, will rapidly increase the pharmacological uses of this receptor. Such tools will allow investigations of the function of GPR35. The disease areas highlighted in this review (Table 2) are all active topics for research with unmet clinical need. This is likely to result in rapid progress in efforts to validate GPR35 as a therapeutic target. Although only approximately 20 publications directly address the expression, pharmacology and function of this receptor, this number is likely to increase as pharmacological tools that modulate the activity of GPR35 become widely available and the potential of GPR35 as a therapeutic target becomes better appreciated.
    Introduction In the last few years it has been proposed that kynurenic Psalmotoxin 1 (KYNA) is the endogenous ligand of the G-protein coupled receptor 35 (GPR35), a newly discovered molecular structure that shares homology with the purinergic receptors GPR-23/P2Y9, with the receptor for nicotinic acid (HM-74) and with GPR-55, an orphan receptor that binds to endocannabinoids (O’Dowd et al., 1998, Wang et al., 2006). GPR35 is coupled to Gi proteins and is highly expressed in the gastro-intestinal tract and the leukocytes but is also present in the CNS (Wang et al., 2006). Zaprinast, a compound formerly known as a cGMP phosphodiesterase inhibitor, has been found to have a particularly high affinity for GPR35 and is considered an useful tool to study this receptor function (Taniguchi et al., 2006). Stimulation of GPR35 heterologously expressed in rat sympathetic neurons inhibits N-type calcium channels, suggesting a potential role for GPR35 in regulating neuronal excitability and transmitter release (Guo et al., 2008). Stimulation of GPR35 with kynurenic acid causes firm arrest of leukocytes to vascular endothelium (Barth et al., 2009) suggesting a role of the receptor in inflammatory states. Since preliminary data suggest that GPR35 is also expressed in the dorsal root ganglia (DRG) we attempted to confirm this observation, to evaluate the presence of GPR35 transcripts in the spinal cord and to evaluate the possible importance of the receptor in the control of inflammatory pain. To test this hypothesis we used a model widely accepted for this purpose: the acetic acid-induced writes in mice and we activated GPR35 with either zaprinast or KYNA. Zaprinast was systemically administered at relatively low doses. Since KYNA poorly crosses the blood brain barrier (Lou et al., 1994), we managed to increase KYNA levels in brain and spinal cord by systemically administering its precursor kynurenine or by inhibiting its disposal from brain and plasma with probenecid (Moroni et al., 1988b, Chiarugi et al., 1996). Kynurenine is the primary degradation product of tryptophan and the origin of the “kynurenine pathway”, a cascade of enzymatic steps that generate several biologically active compounds including KYNA (see: (Moroni, 1999) for a review). Interest in KYNA actions in the brain and spinal cord originated in the late seventies when Lapin and its group reported that systemic or intracerebral administration of the compound could prevent different types of seizures (Lapin, 1976, Lapin, 1980). In the early eighties it was observed that micromolar concentrations of KYNA may selectively antagonize NMDA receptors (Perkins and Stone, 1982) and reduce excitotoxic neuronal damage (Foster et al., 1984). A few years later it was shown that KYNA is present in the central nervous system and that its extracellular or cerebrospinal fluid concentrations range from 15 to 150 nM (Turski et al., 1988, Moroni et al., 1988b, Swartz et al., 1990). It was also shown that brain KYNA is mostly synthesized in glial cells, has a relatively fast turnover rate and significantly accumulates during the aging process (Moroni, 1999, Schwarcz and Pellicciari, 2002). Kynurenine aminotransferases, the enzymes responsible for KYNA synthesis, have a rather low affinity for their substrate (in the mM range) and therefore kynurenine availability is the main factor controlling the rate of KYNA formation and its local concentration (Moroni et al., 1988a, Speciale et al., 1989, Carpenedo et al., 2002). Since kynurenine, beside being the KYNA precursor, may have a number of other effects (Wang et al., 2010), we also tested probenecid that inhibits KYNA disposal.