Stable Peptide Compounds for CB1 Agonist Side-Effect Reduction
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Solution Overview
Problem
Existing CB1 receptor agonists, such as THC, provide effective pain relief but are associated with undesirable side effects like memory impairment and anxiety alterations due to the formation of CB1R and 5-HT2AR heteromers, and current peptides are inefficient in disrupting these heteromers and have stability issues.
Innovation Solution
Development of novel synthetic peptides with specific amino acid sequences, including D-Trp-D-Leu-D-Ile-D-Tyr-D-Met-D-Ala-D-Tyr-D-Val-D-Ala-Gly-D-Ile-D-Leu-D-Lys-D-Arg-D-Trp-NH2, which efficiently disrupt CB1R and 5-HT2AR heteromers, have higher hydrolytic stability, and can penetrate the blood-brain barrier.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CB1 receptor agonists are used to treat pain, then analgesic effects are improved, but memory impairment and anxiety alterations occur due to heteromer formation
Solution Approach 1:
The patent extracts and disrupts the harmful CB1R-5-HT2AR heteromer complex from the brain, specifically removing the pathological interaction while preserving the beneficial analgesic effects of CB1R agonists. The peptide compound selectively binds to and destabilizes the heteromer structure, separating the harmful psychoactive effects from the therapeutic pain relief.
Solution Approach 2:
The peptide compound acts as an intermediary agent that interferes with the formation and stability of the CB1R-5-HT2AR heteromer. By introducing this third component, the patent prevents the direct pathological interaction between CB1R and 5-HT2AR, thereby eliminating memory impairment and anxiety alterations while maintaining analgesic efficacy.
2Object-affected harmful factors
If peptides are used to disrupt CB1R and 5-HT2AR heteromers, then side effects are reduced, but hydrolytic stability and BBB penetration are insufficient
Solution Approach 1:
The patent applies parameter changes by modifying the peptide's chemical structure through D-amino acid incorporation and cyclization. These structural parameter changes confer resistance to proteolytic degradation (improving hydrolytic stability) and enhance the peptide's ability to cross the blood-brain barrier, thereby resolving the previous limitations.
Solution Approach 2:
The patent creates a composite peptide structure combining multiple functional elements: D-amino acids for stability, cyclic structures for conformational rigidity, and specific sequence motifs for BBB penetration. This composite design integrates multiple properties into a single molecule that simultaneously achieves heteromer disruption, stability, and brain delivery.
3Object-affected harmful factors
If existing peptides are used to disrupt heteromers, then some side effects are reduced, but efficiency in disrupting heteromers is insufficient
Solution Approach 1:
The patent optimizes the peptide sequence parameters by incorporating specific D-amino acid residues and cyclic structures that enhance binding affinity and stability. These parameter optimizations result in significantly improved heteromer disruption efficiency compared to previous peptide designs, achieving more effective side effect reduction.
Data Source
AI summary
The present invention relates to compounds of formula (I)(I)AA1-AA2-D-Ile-AA3-D-Met-D-Tyr-D-Ala-D-Tyr-D-Val-D-Ala-Gly-D-Ile-D-Leu-D-Lys-D-Arg-D-Trp-NH2or a pharmaceutically acceptable salts thereof, to processes for their obtention and to their therapeutic indications.