Method of screening for non-steroidal neuropsychiatric agents

• US 6,740,500 B1
• Filed: 03/23/2000
• Issued: 05/25/2004
• Est. Priority Date: 03/23/2000
• Status: Expired due to Fees

• Current Assignee: Doncho P. Uzunov, John M. Davis
• Original Assignee: Doncho P. Uzunov, John M. Davis
• Inventors: Davis, John M., Uzunov, Doncho P.
• Primary Examiner(s): Eyler, Yvonne
• Assistant Examiner(s): BRANNOCK, MICHAEL T
• Application Number:
  US09/534,831
• Time in Patent Office: 1,524 Days
• Field of Search: 435/25, 435/6, 435/7.1, 435/7.21, 435/69.1, 436/501, 530/350, 536/23.1, 514/2
• US Class Current: 435/25
• CPC Class Codes: C12Q 1/26 involving oxidoreductase
• CPC Class Codes: G01N 33/6896 Neurological disorders, e.g. Alzheimer's disease
• CPC Class Codes: G01N 33/743 Steroid hormones

Abstract

A method of screening for non-steroidal neuropsychiatric agents includes determining the ability of a candidate non-steroidal agent to selectively regulate or alter the central nervous system content and/or bioavailability of an endogenous neuroactive steroid. In particular, the method includes determining the ability of the agent to selectively regulate a rate-limiting step in the bio-control of the bioavailable amount of an endogenous neuroactive steroid, wherein the rate-limiting step may be either a step in biosynthesis of an endogenous neuroactive steroid, such as allopregnanolone, or a step in the biodegradation of such an endogenous neuroactive steroid. Alternatively, the method may include determining the ability of a candidate agent in selectively regulating the rate of reuptake of an endogenous neuroactive steroid by neurons or glial cells.

Claims

1. A method of screening for non-steroidal neuropsychiatric agents comprising:

providing a plurality of candidate non-steroidal agents not known to be neuropsychiatric agents;

for each candidate non-steroidal agent, determining the ability of the candidate non-steroidal agent to selectively increase the central nervous system content and/or bioavailability of endogenous allopregnanolone, wherein the determination comprises administering the candidate non-steroidal agent to a subject and measuring the effect of the agent on the central nervous system content and/or bioavailability of allopregnanolone in the subject, wherein an increase in the central nervous system content and/or bioavailability of endogenous allopregnanolone is predictive that the agent is a neuropsychiatric agent.

2. The method of claim 1, wherein the determining includes determining the ability of the agent to selectively regulate a rate-limiting step in the bio-control of the bioavailable amount of endogenous allopregnanolone.

3. The method of claim 2, wherein the rate-limiting step is a step in the biodegradation of endogenous allopregnanolone.

4. The method of claim 3, wherein the rate-limiting step includes inhibition of the oxidative function of the 3α

-hydroxysteroid oxidoreductase that converts allopregnanolone to 5α

-dihydroprogesterone.

5. The method of claim 2, wherein the rate limiting step includes steps in both the biosynthesis and the biodegradation of endogenous allopregnanolone.

6. The method of claim 1, wherein the determining includes determining the ability of the agent to affect degradation of allopregnanolone to 5α

-dihydroprogesterone.

7. A method of screening for non-steroidal neuropsychiatric agents comprising:

providing a plurality of candidate non-steroidal agents not known to be neuropsychiatric agents;

for each candidate non-steroidal agent, determining the ability of the candidate non-steroidal agent to inhibit the oxidative function of the 3α

-hydroxysteroid oxidoreductase that converts allopregnanolone to 5α

-dihydroprogesterone, wherein an increase in the central nervous system content and/or bioavailability of endogenous allopregnanolone is predictive that the agent is a neuropsychiatric agent.