JP2005523418A5 - - Google Patents

Claims (30)

Agent A method of determining useful for stimulating lipolysis in mammals, includes determining whether the agent is an agonist of a high affinity CGRP receptors, said method.   2. The method of claim 1, further comprising determining that the agent preferentially stimulates a high affinity CGRP receptor relative to a metabolic amylin receptor. Comparing the EC _{50 of the} drug with respect to affecting the response mediated by metabolic amylin receptors and the EC _{50 of the} drug with respect to affecting the response mediated by high affinity CGRP receptors. The method of claim 2, further comprising: The The EC ₅₀ values are measured in vitro using the isolated skeletal muscle The method of claim 3.   4. The response mediated by high affinity receptors is an increase in free fatty acids in skeletal muscle tissue and the response mediated by metabolic amylin receptors is an effect on glucose metabolism. Method. below:
(i) determining whether the drug stimulates lipolysis in mammalian tissue expressing a high affinity CGRP receptor and a metabolic amylin receptor; and
(ii) determining whether the drug of (i ) above preferentially stimulates a high affinity CGRP receptor compared to a metabolic amylin receptor;
A method for determining whether an agent is useful as a therapeutic agent , wherein an agent that preferentially stimulates a high affinity CGRP receptor is determined to be useful as a therapeutic agent , Method.   7. The method of claim 6, wherein the tissue is skeletal muscle. A method for determining whether an agent is useful for stimulating lipolysis in a mammal , comprising comparing the lipolytic activity of the agent to the lipolytic activity of CGRP. A method for determining whether an agent is useful for stimulating lipolysis in a mammal , comprising comparing the lipolytic activity of the agent to the lipolytic activity of CGRP. A method for determining a dosage or dosage form of an agonist of a high affinity CGRP receptor that stimulates lipolysis in a skeletal muscle of a mammal without revealing unwanted side effects in the mammal, The side effects of are blood glucose, increased blood lactate levels, or vasodilation, the following:
(i) Below:
a) administering a plurality of different doses or dosage forms of the CGRP receptor agonist to a laboratory mammal;
b) Measure the effect of each dose or dosage form on lipolysis in the tissue of the experimental mammal and measure the effect of each dose on the side effects, thereby providing dose-response data for lipolysis and side effects Create
Performing a dose-response assay by
ii) From the dose-response data, determine the dose of a CGRP receptor agonist formulation that stimulates lipolysis but does not manifest the side effects;
Said method comprising:   11. The method of claim 10, wherein the effect of each dose or dosage form on the lipolysis is determined by measuring free fatty acid levels in the animal tissue. A pharmaceutical composition in unit dosage form for administration to a mammal, wherein the unit dosage is sufficient to preferentially stimulate a high affinity receptor relative to a metabolic amylin receptor. agonist high-affinity CGRP receptor in an amount sufficient to result in a blood agonist levels, and includes excipients that are pharmaceutically acceptable, said pharmaceutical composition.   13. A pharmaceutical composition in unit dosage form according to claim 12, wherein the agonist is CGRP-1 or a biologically functional variant thereof.   13. A pharmaceutical composition in unit dosage form according to claim 12, wherein the agonist is CGRP-1 and the blood agonist level is less than 300 pM. Wherein the agonist is CGRP-1, and blood agonist level is between about 10 ^-15 M to about 10 ^-10 M, a pharmaceutical composition in unit dosage form of claim 12. A therapeutic agent for a mammal suffering from or susceptible to a disease characterized by lipid accumulation in skeletal muscle, including CGRP, wherein the agent is less than 300 pM when administered to a mammal. The agent, which results in a blood agonist level. The drug according to claim 16, wherein the disease is diabetes, insulin resistance, or syndrome X. A therapeutic agent for a mammal suffering from or susceptible to a disease characterized by lipid accumulation in skeletal muscle , including CGRP, wherein the agent is about 10 ⁻ when administered to a mammal. ¹⁵ to cod also blood agonist level between M~ about 10 ^-10, wherein the agent. A therapeutic agent for a mammal suffering from or susceptible to a disease characterized by lipid accumulation in skeletal muscle , comprising a high affinity CGRP receptor agonist , wherein the drug is administered to the mammal Said agent that , when done , provides an agonist level in said mammal that is sufficient to preferentially stimulate a high affinity receptor as compared to a metabolic amylin receptor. 20. A medicament according to claim 19, wherein the agonist is CGRP-1.   A method of stimulating lipolysis in a mammalian isolated cell or tissue, wherein said cell or tissue is contacted with an agonist of a high affinity CGRP receptor and / or metabolic amylin receptor, and said tissue Measuring said change in lipolysis level in said method.   22. The method of claim 21, wherein the change in lipolysis level is detected as a change in free fatty acid content. A method of stimulating lipolysis in an isolated cell or tissue of a mammal, said method comprising contacting said cell or tissue with an agonist of a high affinity CGRP receptor, wherein said tissue Is derived from skeletal muscle or liver, and the tissue is contacted with an effective amount of an agonist to preferentially stimulate the activity of a high affinity CGRP receptor relative to a metabolic amylin receptor , Said method.   24. The method of claim 23, wherein the agonist is CGRP-1. The amount of the CGRP-1 is between about 10 ^-15 M to about 10 ^-10 M, The method of claim 24.   24. The method of claim 23, further comprising detecting a lipolytic stimulus in the tissue. A method of inhibiting lipolysis in an isolated skeletal muscle or liver of a mammal, wherein said skeletal muscle or liver has a sufficient amount of metabolic amylin receptor and / or high affinity to inhibit lipolysis. comprising contacting an antagonist of sex CGRP receptor, said method. 28. The method of claim 27, wherein the antagonist is ^8,37 amylin or ^8,37 CGRP. A method of stimulating lipolysis in mammalian skeletal muscle , the method comprising contacting the tissue with an agonist of a metabolic amylin receptor.   30. The method of claim 29, wherein the agonist is CGRP.