ear-2

GAT229 is a positive allosteric modulator of cannabinoid receptor 1 (CB1) and the S-(-) enantiomer of the CB1 modulator GAT211. It does not activate the receptor on its own but enhances the binding and activity of CB agonists. GAT229 (1 μM) enhances the binding of the CB1 full agonist CP 55,940 to CHO cells expressing human recombinant CB1 (hCB1), as well as the activity of 2-arachidonoyl glycerol , arachidonoyl ethanolamide , and CP 55,940 in arrestin2 recruitment assays and increases ERK1 2 and PLCβ3 phosphorylation in HEK293 cells expressing hCB1. GAT229 (1 μM) enhances depolarization-induced suppression of excitation but does not inhibit excitatory postsynaptic currents (EPSCs) in murine autaptic hippocampal neurons. GAT229 (0.2%, topical) reduces intraocular pressure by 5.8 and 7.7 mm Hg after 6 and 12 hours, respectively, in a transgenic mouse model of ocular hypertension using nose, ear, eye mutation (nee) mice.

α-Melanocyte-stimulating hormone (α-MSH) is a 13-amino acid peptide hormone produced by post-translational processing of proopiomelanocortin (POMC) in the pituitary gland, as well as in keratinocytes, astrocytes, monocytes, and gastrointestinal cells.1It is an agonist of melanocortin receptor 3 (MC3R) and MC4R that induces cAMP production in Hepa cells expressing the human receptors (EC50s = 0.16 and 56 nM, respectively).2α-MSH (100 pM) reducesS. aureuscolony formation andC. albicansgerm tube formationin vitro.3It inhibits endotoxin-, ceramide-, TNF-α-, or okadaic acid-induced activation of NF-κB in U937 cells.1α-MSH reduces IL-6- or TNF-α-induced ear edema in mice.4It also prevents the development of adjuvant-induced arthritis in rats and increases survival in a mouse model of septic shock. Increased plasma levels of α-MSH are positively correlated with delayed disease progression and reduced death in patients with HIV.1 1.Catania, A., Airaghi, L., Colombo, G., et al.α-melanocyte-stimulating hormone in normal human physiology and disease statesTrends Endocrinol. Metab.11(8)304-308(2000) 2.Miwa, H., Gantz, I., Konda, Y., et al.Structural determinants of the melanocortin peptides required for activation of melanocortin-3 and melanocortin-4 receptorsJ. Pharmacol. Exp. Ther.273(1)367-372(1995) 3.Cutuli, M., Cristiani, S., Lipton, J.M., et al.Antimicrobial effects of a-MSH peptidesJ. Leukoc. Biol.67(2)233-239(2000) 4.Lipton, J.M., Ceriani, G., Macaluso, A., et al.Antiiinflammatory effect of the neuropeptide a-MSH in acute, chronic, and systemic inflammationAnn. N.Y. Acad. Sci.25(741)137-148(1994)

GM 1489 is a broad-spectrum inhibitor of matrix metalloproteinases (MMPs) with Ki values of 0.002, 0.1, 0.5, 0.2, and 20 μM for MMP-1, MMP-8, MMP-2, MMP-9, and MMP-3, respectively. It reduces 5-aza-2'-deoxycytidine-induced increases in MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, and MMP-14 expression as well as cell invasion in AsPC-1, BxPC-3, Hs766T, MiaPaCa2, and PANC-1 cancer cells. Topical administration of GM 1489 (100 μg) inhibits increases in ear thickness and epidermal hyperplasia induced by phorbol 12-myristate 13-acetate and phorbol dibutyrate (PdiBu) in mice.

Betulonaldehyde is a pentacyclic triterpenoid and derivative of the cholesterol biosynthesis inhibitor betulin that has been found in Betula. It is active against P. falciparum (IC50 = 3.36 µg ml) and cytotoxic to NCI H187 lung cancer cells and non-cancerous Vero cells (IC50s = 19.23 and 17.09 µg ml, respectively). Topical application of betulonaldehyde (1 mg ear) reduces ear edema induced by phorbol 12-myristate 13-acetate (TPA; Item No. 10008014) in mice. It has also been used a precursor in the semisynthesis of C-2 and C-28 betulonic aldehyde derivatives.

APC 366 是肥大细胞类胰蛋白酶 (tryptase) 的选择性抑制剂，Ki 值为7.1 μM。在羊过敏性哮喘模型中，APC 366 抑制抗原诱导的早期哮喘反应 (EAR)、晚期哮喘反应 (LAR) 和支气管高反应性 (BHR)。

Necrostatin 2 是一种坏死蛋白和受体相互作用蛋白激酶1（RIPK1）抑制剂，可用于研究突发性耳聋、头晕和耳鸣等内耳疾病。

COX-2-IN-14 (compound 2a) is a highly potent and selective inhibitor of COX-2 (cyclooxygenase-2), with strong binding affinity at the active site of COX-2 co-crystal. Demonstrating remarkable in vivo anti-inflammatory activity, COX-2-IN-14 effectively reduces ear edema and myeloperoxidase (MPO) activity in mice [1].

Cytosolic phospholipase A2α (cPLA2α) specifically catalyzes the hydrolysis of arachidonic acid from thesn-2-ester position of membrane phospholipids, playing a central role in initiating the synthesis of prostaglandins and leukotrienes, both important mediators of the inflammatory process.1CAY10641 is an inactive alcohol derivative of a highly potent (IC50= 12 nM) cPLA2α inhibitor.2The parent compound demonstrates strong anti-inflammatory effects when applied topically at a dose of 0.1 mg ear in a mouse model of acute irritant contact dermatitis.2CAY10641 is rapidly cleared from the blood stream (only 0.5 μg ml remains 30 minutes after 10 mg kg intravenous administration to mice).2However, no other biological effects have been reported. 1.Schaloske, R.H., and Dennis, E.A.The phospholipase A2 superfamily and its group numbering systemBiochemica et Biophysica Acta17611246-1259(2006) 2.Drews, A., Bovens, S., Roebrock, K., et al.1-(5-carboxyindol-1-yl)propan-2-one inhibitors of human cytosolic phospholipase A2α with reduced lipophilicity: Synthesis, biological activity, metabolic stability, solubility, bioavailability, and topical in vivo activityJournal of Medicinal Chemistry535165-5178(2010)