Method for measuring alpha value of muscarinic M1 receptor positive allosteric modulators
AssigneeTakeda Pharmaceutical Company Limited
InventorsHaruhide Kimura, Yuu Sako, Satoru Matsuda, Yuji Shimizu, Emi Kurimoto, Takao Mandai
Life of this patent
Estimating the term…
Abstract
The present invention provides a useful and efficient screening method for finding a cholinergic muscarinic M1 receptor positive allosteric modulator (M1PAM) with reduced cholinergic side effects. The present invention also provides a method for treating Alzheimer's disease and the like, a method for reducing cholinergic side effects, and the like which use M1PAM selected by the screening method and having a low α value, or the M1PAM and an acetylcholinesterase inhibitor.
Claims12
A method for screening for a cholinergic muscarinic M1 receptor (M1R) positive allosteric modulator (M1PAM) with reduced cholinergic side effects, comprising the following steps (a) to (c):
- (a) contacting M1R or a partial peptide thereof with a test compound, acetylcholine (ACh) and detectable M1 antagonist,
- (b) measuring α value of the test compound, wherein the α value is calculated as αAB from numeric formula (ii):
- Y
- =
- [
- C
- ]
- K
- C
- +
- α
- BC
- [
- B
- ]
- [
- C
- ]
- K
- B
-
- K
- C
- 1
- +
- [
- A
- ]
- K
- A
- +
- [
- B
- ]
- K
- B
- +
- [
- C
- ]
- K
- C
- +
- α
- AB
- [
- A
- ]
- [
- B
- ]
- K
- A
-
- K
- B
- +
- α
- AB
- [
- B
- ]
- [
- C
- ]
- K
- B
-
- K
- C
- ;
- (
- ii
- )
- wherein Y is the percentage of specific binding;
- [A], [B], and [C] are respectively the concentration of ACh, the test compound and detectable M1 antagonist;
- KA, KB and Kc respectively show the equilibrium dissociation constant of ACh, the test compound and detectable M1 antagonist;
- and
- αAB and αBC are respectively the cooperativities between the test compound and ACh, and the test compound and detectable M1 antagonist,
- (c) repeating steps (a) and (b) to screen one or more test compounds and selecting one or more of the test compounds with a low α value, each as an MIPAM, wherein the low a value is associated with reduced cholinergic side effects, and wherein the low α value is greater than 1 and not more than 500, and wherein the M1PAM with reduced cholinergic side effects has not less than 2-fold safety margin between a minimal cognition effective dose and a minimal cholinergic side effect dose in mammals.
A method for screening for a cholinergic muscarinic M1 receptor (M1R) positive allosteric modulator (M1PAM) with reduced cholinergic side effects, comprising the following steps (a) to (c):
- (a) contacting M1R or a partial peptide thereof with a test compound and detectable ACh,
- (b) measuring α value of the test compound, wherein the α value is calculated from numeric formula (i);
- Y
- =
- [
- A
- ]
- K
- A
- +
- α
- [
- A
- ]
- [
- B
- ]
- K
- A
-
- K
- B
- 1
- +
- [
- A
- ]
- K
- A
- +
- [
- B
- ]
- K
- B
- +
- α
- AB
- [
- A
- ]
- [
- B
- ]
- K
- A
-
- K
- B
- ;
- (
- i
- )
- where Y is the percentage of specific binding;
- [A] and [B] are respectively the concentration of detectable ACh and the test compound;
- KA and KB are respectively the equilibrium dissociation constant of detectable ACh and the test compound;
- and
- α is the cooperativity between the test compound and detectable ACh,
- (c) repeating steps (a) and (b) to screen one or more test compounds and selecting one or more of the test compounds with a low α value, each as an MIPAM, wherein the low α value is associated with reduced cholinergic side effects, and wherein the low α value is greater than 1 and not more than 500, and wherein the M1PAM with reduced cholinergic side effects has not less than 2-fold safety margin between a minimal cognition effective dose and a minimal cholinergic side effect dose in mammals.
A method for screening for a cholinergic muscarinic M1 receptor (M1R) positive allosteric modulator (M1PAM) with reduced cholinergic side effects, comprising the following steps (a) to (c):
- (a) contacting M1R or a partial peptide thereof with a test compound, ACh, and detectable M1PAM,
- (b) measuring α value of the test compound, wherein the α value can be calculated as αAB from numeric formula (iii):
- Y
- =
- [
- C
- ]
- K
- C
- +
- α
- AC
- [
- A
- ]
- [
- C
- ]
- K
- A
-
- K
- C
- 1
- +
- [
- A
- ]
- K
- A
- +
- [
- B
- ]
- K
- B
- +
- [
- C
- ]
- K
- C
- +
- α
- AB
- [
- A
- ]
- [
- B
- ]
- K
- A
-
- K
- B
- +
- α
- AC
- [
- A
- ]
- [
- C
- ]
- K
- A
-
- K
- C
- ;
- (
- iii
- )
- wherein Y is the percentage of specific binding;
- [A], [B], and [C] are respectively the concentration of ACh, the test compound and detectable M1PAM;
- KA, KB and KC respectively show the equilibrium dissociation constant of ACh, the test compound and detectable M1PAM;
- and
- αAB and αAC are respectively the cooperativities between ACh and the test compound, and ACh and detectable M1PAM,
- (c) repeating steps (a) and (b) to screen one or more test compounds and selecting one or more of the test compounds with a low α value, each as an MIPAM, wherein the low α value is associated with reduced cholinergic side effects, and wherein the low α value is greater than 1 and not more than 500, and wherein the M1PAM with reduced cholinergic side effects has not less than 2-fold safety margin between a minimal cognition effective dose and a minimal cholinergic side effect dose in mammals.
Dependencies are inferred from the claim text.