Quinolinyl- and phenantridinyl-acetamides as bradykinin B1 receptor antagonists.

A new series of quinolinyl- and phenantridinyl-acetamides were synthesizer and evaluated against bradykinin B1 receptor. In vitro metabolic stability data were reported for the key compounds.The analgesic effect of compound 20 from the phenantridine series was proved in-vivo.

Cariprazine (RGH-188), a dopamine D(3) receptor-preferring, D(3)/D(2) dopamine receptor antagonist-partial agonist antipsychotic candidate: in vitro and neurochemical profile.

Cariprazine {RGH-188; trans-N-[4-[2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl]cyclohexyl]-N',N'-dimethylurea hydrochloride}, a novel candidate antipsychotic, demonstrated approximately 10-fold higher affinity for human D(3) versus human D(2L) and human D(2S) receptors (pKi 10.07, 9.16, and 9.31, respectively). It displayed high affinity at human serotonin (5-HT) type 2B receptors (pK(i) 9.24) with pure antagonism. Cariprazine had lower affinity at human and rat hippocampal 5-HT(1A) receptors (pK(i) 8.59 and 8.34, respectively) and demonstrated low intrinsic efficacy. Cariprazine displayed low affinity at human 5-HT(2A) receptors (pK(i) 7.73). Moderate or low affinity for histamine H(1) and 5-HT(2C) receptors (pK(i) 7.63 and 6.87, respectively) suggest cariprazine's reduced propensity for adverse events related to these receptors. Cariprazine demonstrated different functional profiles at dopamine receptors depending on the assay system. It displayed D(2) and D(3) antagonism in [(35)S]GTPgammaS binding assays, but stimulated inositol phosphate (IP) production (pEC(50) 8.50, E(max) 30%) and antagonized (+/-)-quinpirole-induced IP accumulation (pK(b) 9.22) in murine cells expressing human D(2L) receptors. It had partial agonist activity (pEC(50) 8.58, E(max) 71%) by inhibiting cAMP accumulation in Chinese hamster ovary cells expressing human D(3) receptors and potently antagonized R(+)-2-dipropylamino-7-hydroxy-1,2,3,4-tetrahydronaphtalene HBr (7-OH-DPAT)-induced suppression of cAMP formation (pK(b) 9.57). In these functional assays, cariprazine showed similar (D(2)) or higher (D(3)) antagonist-partial agonist affinity and greater (3- to 10-fold) D(3) versus D(2) selectivity compared with aripiprazole. In in vivo turnover and biosynthesis experiments, cariprazine demonstrated D(2)-related partial agonist and antagonist properties, depending on actual dopaminergic tone. The antagonist-partial agonist properties of cariprazine at D(3) and D(2) receptors, with very high and preferential affinity to D(3) receptors, make it a candidate antipsychotic with a unique pharmacological profile among known antipsychotics.

Topical analgesic, anti-inflammatory and antioxidant properties of Oxybaphus nyctagineus: phytochemical characterization of active fractions.

ETHNOPHARMACOLOGICAL RELEVANCE: Oxybaphus nyctagineus (Michx.) Sweet has traditionally been used by several Native American tribes predominantly as a topical anti-inflammatory and analgesic agent. AIM OF THE STUDY: To evaluate the antioxidant, analgesic and anti-inflammatory activity of the extracts prepared from the aerial parts of Oxybaphus nyctagineus and to characterize the major chemical constituents of the bioactive extracts. MATERIALS AND METHODS: Crude polar and apolar extracts (PCE and ACE) of the herb of Oxybaphus nyctagineus were prepared and tested in the models of the CFA-induced hyperalgesia in rat knee and carrageenan-induced paw edema in rat. To identify the active compounds, subfractions were prepared by column chromatography and subjected in vitro assays, such as antioxidant assays (DPPH, peroxynitrite (ONOO-) scavenging), and the LPS-induced IL-1ß release test in human monocytes. Preparative HPLC was employed for the isolation of active substances, while phytochemical analysis was performed by mean of LC-MS/MS and NMR. RESULTS: The topically administered PCE and ACE of Oxybaphus nyctagineus demonstrated a significant analgesic and anti-inflammatory effect in the inflammation animal models. The subfraction A4 of ACE and the subfraction P5 of PCE considerably inhibited the LPS-induced IL-1ß release in human monocytes, while the strongest activity was localized in the subfraction P5 in the antioxidant assays. The HPLC-MS/MS and NMR analysis revealed that 6-methoxyflavonol diglycosides, namely patuletin-3-O-robinobioside (1), 6-methoxykaempferol-3-O-robinobioside (2), spinacetin-3-O-robinobioside (3), and hydroxy-polyenoic fatty acids, namely corchorifatty acid B (4), 9-hydroxy-10E,12Z,15Z-octadecatrienoic acid (9-HOT acid) (5), and 9-hydroxy-10E,12Z-octadecadienoic acid (9-HOD acid) (6) were present in PCE, and in ACE as major compounds. CONCLUSION: The results of this study established a pharmacological evidence for the traditional use of Oxybaphus nyctagineus as an anti-inflammatory agent used topically, and provided data on its phytochemical composition for the first time.