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    • PPM-18 Screening of the compounds allowed

    2021-12-02

    Screening of the compounds allowed for a number of interesting SAR observations. First of all, pyridyl analogue demonstrated that a pyridine ring would be beneficial for both log as well as increasing the potency (entry 2 versus entry 1). Electron-poor aryl groups next to the oxadiazolone were detrimental (), but electron-rich groups were also not beneficial (entry 3). As discussed earlier, it was anticipated that the more electron-rich aryl groups next to the oxadiazolone would be beneficial electronically, but the results obtained could be validated by the electron-donating groups being larger and creating some detrimental steric interactions. It was found that electron-rich cyclopropylaryl groups had relatively good activities (entry 7), but also typically had solubility problems (entries 5 and 6). Fortunately, analogue was soluble, but the moderate activity illustrates that the -methoxy group is detrimental since the most closely related analogue (ML191, ) was more active and the electron-withdrawing -chloro analogue () was even more active. Dichlorophenyl analogue had good activity, but was not as potent as compared to the monochloroaryl compound (entries 8 and 9) which could be justified based on the larger steric bulk of the second chlorine atom. Structure with the dimethylcyclopropyl group was similarly active (entry 10) as compared to the parent compound, ML191 () which is interesting since this compound adds more steric bulk to the cyclopropyl aryl section of the molecule, albeit in a slightly different location than analogue . It should be noted that analogue is the only structure analysed that is chiral. The synthesis of was racemic and the model indicates that there are no major anticipated differences in activities between the two enantiomers.
    Introduction Many G-protein coupled receptors involved in pain and addiction are pharmacologically and biochemically well characterized, but some orphan receptors like GPR35 and GPR55, with homology to known receptors for drugs of abuse, remain poorly characterized. GPR35 is emerging as an important target in pain (spinal antinociception as well as inflammatory pain), heart disease, asthma, inflammatory bowel disease and cancer, areas with unmet medical needs. To date, quite a few agonists and antagonists have been discovered for GPR35 (Heynen-Genel et al., 2010c, Milligan, 2011). While kynurenic PPM-18 was suggested to be an endogenous ligand for GPR35, so was 2-arachidonyl lysophosphatidic acid (LPA) (Oka et al., 2010, Wang et al., 2006). The GPR55 receptor is a promising target in inflammatory and neuropathic pain (Staton et al., 2008), as well as in bone development (Whyte et al., 2009). While several studies indicate that GPR55 activation is pro-carcinogenic (Andradas et al., 2011, Ford et al., 2010, Pineiro et al., 2011), others report anticarcinogenic activity (Huang et al., 2011). GPR55 has been suggested to be a cannabinoid receptor, but is quite clearly also a receptor for lysophosphatidylinositol (Henstridge et al., 2011, Oka et al., 2007, Ryberg et al., 2007, Sharir and Abood, 2010). Recently, additional agonists and antagonists have been discovered for GPR55 (Brown et al., 2011, Heynen-Genel et al., 2010a, Heynen-Genel et al., 2010b). Here, we review what is known about GPR35 and GPR55 and their relationships to cannabinoid and lysophospholipid receptors.
    Expression profiles of GPR35 and GPR55 GPR35 was first identified in 1998 from rat intestine as a class A (rhodopsin-like) G protein-coupled receptor that contains 309 amino acids (O'Dowd et al., 1998). A splice variant, GPR35b, containing an N-terminal expansion of 31 amino acids was later discovered from a cDNA library produced from human gastric cancer cells (Okumura et al., 2004). Because GPR35b was able to transform NIH-3T3 cells, it was suggested that it might be oncogenic and play a role in gastric cancer development (Okumura et al., 2004). The significant expression of GPR35 in human small intestine, colon and stomach was confirmed subsequently by Imielinski et al. in 2009 (Imielinski et al., 2009). Other rat tissues also express GPR35, such as lung, uterus, dorsal root ganglion (Ohshiro et al., 2008, Taniguchi et al., 2006) and spinal cord (Cosi et al., 2011). Wang et al. reported GPR35 expression in the spleen and white cells of both human and mice (Wang et al., 2006). Furthermore human mast cells, basophils and eosinophils also express GPR35 (Yang et al., 2010). GPR35 expression in immune cells was later expanded to peripheral monocytes and primary macrophages as well (Barth et al., 2009, Sparfel et al., 2010). In failing heart cells, an enhanced expression of GPR35 was found in a global gene expression profiling study (Min et al., 2010).