Drug-induced activation of the Reelin signaling system

1. A method of treating a disease or disorder of the central nervous system is a selected from a developmental disorder, a cognitive disorder, a degenerative disorder, a neuropsychiatric disorder, or traumatic brain injury in a subject in need thereof comprising, administering to the subject an effective amount of an agonist of a lipoprotein receptor, wherein the lipoprotein receptor is selected from ApoER2 and VLDLR, thereby improving cognitive function, increasing dendritic spine density, improving associative learning, improving special learning, or improving long-term potentiation of neurons, and wherein the agonist is a compound of Formula I:

or a pharmaceutically acceptable salt thereof,

wherein each R 1 is independently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl;

n is an integer from 0 to 5;

Q is C, CH, CH 2 , N, or NH;

Z is C═O, NH, or CH 2 ;

Y is C═O, NH, or CH 2 , or Z and Y may together form a bicyclic ring; and

X is cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, or heteroaryl, and may be unsubstituted or substituted with (R 2 ) m , wherein each R 2 is independently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl, and m is an integer from 0 to 5.

2. The method of claim 1 , wherein the disease or disorder of the central nervous system is the result of a Reelin deficiency.

3. The method of claim 2 , wherein the disease or disorder of the central nervous system is selected from Lissencephaly, fragile X syndrome, William's syndrome, Rett syndrome, Down's syndrome, Angelman syndrome, autism, ischemia, hypoxia, Alzheimer's disease, schizophrenia, bipolar disorder, neurodegeneration, traumatic brain injury, mental retardation, dementia, bipolar disorder, and stroke.

4. The method of claim 1 , wherein the lipoprotein receptor is ApoER2.

5. The method of claim 1 , wherein the lipoprotein receptor is VLDLR.

6. The method of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

7. The method of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

8. The method of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

9. The method of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

10. The method of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

11. The method of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

12. The method of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

13. The method of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

14. The method of claim 1 , wherein the agonist is a compound of Formula II:

or a pharmaceutically acceptable salt thereof,

wherein each R 1 is independently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl;

n is an integer from 0 to 5; and

each R 2 is independently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl; and

m is an integer from 0 to 5.

15. The method of claim 1 , wherein the agonist is a compound of Formula III:

or a pharmaceutically acceptable salt thereof,

wherein each R 1 is independently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl;

n is an integer from 0 to 5; and

each R 2 is independently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl.