1 Release of the tachykinin, substance P, from the peripheral terminals of polymodal afferent C-fibres is thought to be largely responsible for the vasodilatation and plasma protein extravasation described as neurogenic inflammation. The effects of CP-96,345, a non-peptide antagonist at the substance P (NK1) receptor, on these vascular reactions were investigated in the rat. 2 Intravenously (i.v.) injected CP-96,345 (0.4-3.Opmolkg-') prevented the drop in blood pressure, a measure of the peripheral vasodilatation, evoked by substance P and neurokinin A in a dose-and timedependent manner, but did not affect that elicited by the non-tachykinin peptides calcitonin gene-related peptide and vasoactive intestinal polypeptide. 3 Plasma protein extravasation evoked by i.a. infusion of substance P. antidromic stimulation of the saphenous or the vagus nerve, and stimulation of cutaneous afferent nerves with mustard oil, were each significantly inhibited by CP-96,345 (3.0-9.Opmol kg-i.v.). Furthermore, CP-96,345 was orally active in blocking mustard oil-induced plasma extravasation with an ED50 of 10,umol kg-'. 4 The inhibition of substance P-induced vasodilatation and of neurogenic plasma extravasation by CP-96,345 was stereospecific as the inactive isomer CP-96,344 (2R, 3R enantiomer of CP-96,345) had no effect. 5 Thus CP-96,345 is a specific, highly potent, long-acting and orally active inhibitor of tachykininmediated neurogenic inflammation.

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1 The analgesic activity of CP-101,606, an NR2B subunit-selective N-methyl-D-aspartate (NMDA) receptor antagonist, was examined in carrageenan-induced hyperalgesia, capsaicin-and 4b-phorbol-12-myristate-13-acetate (PMA)-induced nociceptive tests in the rat. 2 CP-101,606 30 mg kg 71 , s.c., at 0.5 and 2.5 h after carrageenan challenge suppressed mechanical hyperalgesia without any apparant alternations in motor coordination or behaviour in the rat. 3 CP-101,606 also inhibited capsaicin-and PMA-induced nociceptive responses (licking behaviour) with ED 50 values of 7.5 and 5.7 mg kg 71 , s.c., respectively. 4 These results suggest that inhibition of the NR2B subunit of the NMDA receptor is eective in vivo at modulating nociception and hyperalgesia responses without causing the behavioural side eects often observed with currently available NMDA receptor antagonists.

A highly expressed prostaglandin E 2 (PGE 2) in tumor tissues suppresses antitumor immunity in the tumor microenvironment (TME) and causes tumor immune evasion leading to disease progression. In animal studies, selective inhibition of the prostaglandin E receptor 4 (EP4), one of four PGE 2 receptors, suppresses tumor growth, restoring the tumor immune response toward an antitumorigenic condition. This review summarizes PGE 2 /EP4 signal inhibition in relation to the cancer-immunity cycle (C-IC), which describes fundamental tumor-immune interactions in cancer immunotherapy. PGE 2 is suggested to slow down C-IC by inhibiting natural killer cell functions, suppressing the supply of conventional dendritic cell precursors to the TME. This is critical for the tumor-associated antigen priming of CD8 + T cells and their translocation to the tumor tissue from the tumor-draining lymph node. Furthermore, PGE 2 activates several key immune-suppressive cells present in tumors and counteracts tumoricidal properties of the effector CD8 + T cells. These effects of PGE 2 drive the tumors to non-T-cell-inflamed tumors and cause refractory conditions to cancer immunotherapies, e.g., immune checkpoint inhibitor (ICI) treatment. EP4 antagonist therapy is suggested to inhibit the immune-suppressive and tumorigenic roles of PGE 2 in tumors, and it may sensitize the therapeutic effects of ICIs in patients with non-inflamed and C-IC-deficient tumors. This review provides insight into the mechanism of action of EP4 antagonists in cancer immunotherapy and suggests a C-IC modulating opportunity for EP4 antagonist therapy in combination with ICIs and/or other cancer therapies.

Adenosine is an endogenous neuromodulator that when produced in the central and the peripheral nervous systems has anticonvulsant, anti-inflammatory, and analgesic properties. However, efforts to use adenosine receptor agonists are plagued by dose-limiting cardiovascular side effects. As an alternative, we explored the use of adenosine kinase inhibitors (AKIs) as potential antiseizure agents and demonstrated an adenosine receptor mediated therapeutic effect in the absence of overt cardiovascular side effects. These activities were associated with elevation of extracellular adenosine concentrations due to inhibition of AK in a site and event specific manner. Several tubercidin based AKIs, including the ribo- and lyxo-furanosyltubercidin analogues as well as the newly discovered erythro-furanosyltubercidin analogues, designed to prevent 5'-O-phosphorylation and associated toxicities, were tested for their analgesic activity in the rat formalin paw model. Described herein are the synthesis, enzyme inhibition structure-activity relationships (SARs) of erythro-furanosyltubercidin analogues, and SARs of analgesic activity of various classes of AKIs. Also reported is the characterization of a lead AKI, 19d (GP3966), an orally bioavailable compound (F% = 60% in dog) which exhibits broad-spectrum analgesic activities (ED50 < or = 4 mg/kg, per os) that are reversible with an adenosine receptor antagonist (theophylline).