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WO 2009/117621 Al (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date 24 September 2009 (24.09.2009) WO 2009/117621 Al (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 31/535 (2006.01) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, (21) International Application Number: CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, PCT/US2009/037733 EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, (22) International Filing Date: HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, 19 March 2009 (19.03.2009) KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, (25) Filing Language: English NZ, OM, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, (26) Publication Language: English SK, SL, SM, ST, SV, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: 61/070,1 37 19 March 2008 (19.03.2008) US (84) Designated States (unless otherwise indicated, for every 61/043,084 7 April 2008 (07.04.2008) US kind of regional protection available): ARIPO (BW, GH, 61/048,477 28 April 2008 (28.04.2008) US GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, 61/087,140 7 August 2008 (07.08.2008) US ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, (71) Applicant (for all designated States except US): ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, TYRATECH, INC. [US/US]; 1901 South Harbor City MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK, TR), Blvd., Suite 400, Melbourne, FL 32901 (US). OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). (72) Inventor; and (75) Inventor/Applicant (for US only): ENAN, Essam Published: [US/US]; 1226 Impala Place, Davis, CA 95616 (US). — with international search report (Art. 21(3)) (74) Agent: LAI, Karen, W.; 505 Montgomery Street, Suite 800, San Francisco, CA 94 111 (US). (54) Title: PEST CONTROL COMPOSITIONS AND METHODS Down at 30 cond Post aegypti. (57) Abstract: Embodiments of the present invention provide compositions for controlling a target pest including a first agent and a second agent comprising a pest control product or a signal cascade modulator, wherein the first agent and the second agent act synergistically to control the target pest. The first agent can be capable of interacting with a receptor in the target pest. The pest control product can have a first activity against the target pest when applied without the active agent and the compositions can have a second activity against the target pest; and the second activity can be greater than the first activity. Embodiments of the in vention can include compositions that modulate the signal cascade initiated by the binding of ligands to, for example, cell surface receptors. Methods of screening such compositions are also disclosed. PEST CONTROL COMPOSITIONS AND METHODS FIELD OF THE INVENTION [0001] The present invention relates to compositions and methods related to controlling insects. The invention also relates to compositions and methods for altering and/or disrupting G protein-coupled receptor signaling and cycling resulting in the disruption of normal biology or behavior in invertebrates. BACKGROUND OF THE INVENTION [0002] While the first recorded use of chemicals to control pests dates back to 2500 BC, only in the last 60 years has chemical control has been widely used. Early pesticides included hellebore to control body lice, nicotine to control aphids, and pyrithrin to control a wide variety of insects. Lead arsenate was first used in 1892 as an orchard spray, while at the same time it was discovered that a mixture of lime and copper sulphate (Bordeaux mixture) controlled downy mildew, a fungal disease of grapes. [0003] The modern era of chemical pest control commenced during World War II. For example, DDT played a major role in maintaining the health and welfare of soldiers who used it to control body lice and mosquitoes. Further developments of pesticides followed, and with their relatively low cost, ease of use, and effectiveness, they became the primary means of pest control. Protection of crops, produce, animals, and humans over extended periods became possible with corresponding increases in food production and improved standards of living. [0004] Some modern pesticides are sophisticated compounds that are carefully researched to ensure they are effective against target organisms, generally safe to the environment, and can be used without undue hazard to users or consumers. Many of these have been developed to target specific biochemical reactions within the target organism, e.g. an enzyme necessary for photosynthesis within a plant or a hormone required for normal development in an insect. Thus, some modern chemicals are safer, more specific, and friendlier to the environment than the older products they have replaced. [0005] Furthermore, G protein-coupled receptors (GPCRs) form one of the largest families of integral membrane receptors. GPCRs transduce information provided by extracellular stimuli into intracellular second messengers via their coupling to heterotrimeric G proteins and the subsequent regulation of a variety of effector systems. Therapeutic agents often target GPCRs because of their capability to bind ligands, hormones, and drugs with high specificity. Agonist activation of GPCRs also initiates processes that desensitize GPCR responsiveness and their internalization. [0006] Common to most GPCRs is the cyclic process of signaling, desensitization, internalization, resensitization, and recycling to the plasma membrane. This cycle prevents cells from undergoing excessive receptor stimulation or periods of prolonged inactivity. Mechanisms for desensitization of GPCRs include receptor phosphorylation and subsequent endocytosis, which removes the receptor-ligand complex from the cell surface. As a result of this desensitization process, a common limitation of GPCR-targeted compositions is target organism tolerance or resistance, as receptor desensitization can mute their effectiveness. SUMMARY [0007] The present disclosure relates to embodiments of a composition for controlling a target pest comprising a first agent and a second agent, wherein the first agent has a first activity against the target pest, the second agent has a second activity against the target pest, the composition has a third activity against the target pest, and the third activity reflects a synergistic interaction of the first agent and the second agent. [0008] In a further aspect, the first agent comprises one or more compounds selected from the group consisting of amyl butyrate, trans-anethole, anise star oil, black seed oil, citral, p-cymene, genistein, geraniol, geranyl acetate, isopropyl myristate, d- limonene, linalool, linalyl acetate, lilac flower oil, methyl salicylate, a-pinene, piperonal, piperonyl alcohol, tetrahydrolinalool, thyme oil, thyme oil white, thymol, triethyl citrate, vanillin, and wintergreen oil. [0009] In a further aspect, the first agent is capable of interacting with a receptor in the target pest. [0010] In a further aspect, the receptor is a G protein-coupled receptor. [0011] In a further aspect, the second agent is selected from the group consisting of a pesticide, a fungicide, an herbicide, a nematicide, an insecticide, an acaricide, and a bacteriocide. [0012] In a further aspect, the second agent acts on a molecular target other than the receptor. [0013] In a further aspect, the first agent is capable of interacting with the receptor to trigger, alter, or disrupt a biological function related to the binding of the receptor with the first agent, and the second agent is capable of interacting with a non receptor molecule or step associated with cycling of the receptor, to disrupt the cycling of the receptor. [0014] In a further aspect, the first activity persists for a first period, the second activity persists for a second period, the third activity persists for a third period, and the third period is longer than either the first period or the second period. [0015] In a further aspect, at least one of the first activity and the second activity is essentially zero. [0016] In a further aspect, the target pest is a species belonging to an animal order selected from the group consisting of Acari, Anoplura, Araneae, Blattaria, Blattodea, Coleoptera, Collembola, Diptera, Grylloptera, Hemiptera, Heteroptera, Homoptera, Hymenoptera, Isopoda, Isoptera, Lepidoptera, Mantodea, Mallophaga, Neuroptera, Odonata, Orthoptera, Psocoptera, Rhabditida, Siphonaptera, Symphyla, Thysanura, and Thysanoptera. [0017] In a further aspect, the second agent is a diamide compound. [0018] In a further aspect, the second agent is a spirocyclic phenyl-substituted tetronic acid pesticide. [0019] In a further aspect, the second agent is selected from the group consisting of fϊpronil, clothianidin, imidacloprid, abamectin, forskolin, genistein, yohimbine, fluoxastrobin, flubendiamide and spiromesifen. [0020] In a further embodiment, the second agent comprises fϊ pronil. [0021] In a further aspect of this embodiment, the first agent comprises amyl butyrate and anise star oil. [0022] In a further aspect of this embodiment, amyl butyrate is present within a range of 20%-30%, and anise star oil is present within a range of 40%-60%. [0023] In a further aspect of this embodiment, the first agent comprises geraniol, isopropyl myristate, and thyme oil white. [0024] In a further aspect of this embodiment, geraniol is present within a range of 25%-35%, isopropyl myristate is present within a range of 35%-45%, and thyme oil white is present within a range of 25%-35%. [0025] In a further aspect of this embodiment, the first agent comprises p- cymene, linalool, a-pinene, and thymol.
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