Pregnenolone Derivatives Allosteric CB1 Receptor Modulation

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Solution Overview

Problem

Current CB1 receptor antagonists, such as rimonabant, act as inverse agonists, leading to adverse effects due to total inhibition of receptor activity, necessitating the development of methods that inhibit CB1 receptors without interfering with orthosteric binding and minimizing side effects.

Innovation Solution

The use of pregnenolone and its derivatives, which inhibit CB1 receptor activation by natural or synthetic agonists without modifying orthosteric binding, providing a more physiological mechanism of action and potentially reducing side effects.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If traditional CB1 receptor antagonists (e.g., rimonabant) are used to block CB1 receptor activation, then therapeutic effects for disorders like addiction and metabolic disorders are achieved, but adverse effects occur due to total inhibition of receptor activity

Engineering Contradiction:

Improvetherapeutic effectVSAvoidadverse effects

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent changes the binding mode parameter from orthosteric (traditional antagonists) to allosteric (new compounds), which alters the mechanism of action from total inhibition to modulatory inhibition, thereby reducing adverse effects while maintaining therapeutic benefits

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The new compounds act as intermediary modulators between the agonist and the CB1 receptor, providing a more nuanced control of receptor activation that prevents complete inhibition and associated side effects

Inventive Principle:

Principle #24Intermediary (Mediator)

2Reliability

If orthosteric CB1 receptor antagonists are used to inhibit receptor activity, then CB1 activation is blocked, but orthosteric binding is interfered with

Engineering Contradiction:

Improvereceptor inhibitionVSAvoidinterference with orthosteric binding

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent segments the receptor binding site interaction into two distinct locations: orthosteric site (for endogenous ligands) and allosteric site (for new compounds), allowing simultaneous presence of both ligand types without mutual interference

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The allosteric compounds serve as intermediaries that modulate receptor activity without directly competing with orthosteric ligands, thus avoiding interference with natural binding processes

Inventive Principle:

Principle #24Intermediary (Mediator)

Data Source

PatentEP3170501B1Antagonists of CB1 receptor

Publication Date: 2020.07.08 INST NAT DE LA SANTE & DE LA RECHERCHE MEDICALE (INSERM)

AI summary

The invention relates to an antagonist of CB1 receptor for use in the treatment of a pathologic condition or disorder selected from the group consisting of bladder and gastrointestinal disorders ; inflammatory diseases; cardiovascular diseases; nephropathies; glaucoma ; spasticity ; cancer ; osteoporosis ; metabolic disorders ; obesity ; addiction, dependence, abuse and relapse related disorders; psychiatric and neurological disorders; neurodegenerative disorders ; autoimmune hepatitis and encephalitis ; pain ; reproductive disorders and skin inflammatory and fibrotic diseases.