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Aza-tricyclic substance P antagonists
J A Lowe1, S E Drozda, S McLean
1Central Research Division, Pfizer, Inc., Groton, Connecticut 06340.
Journal of Medicinal Chemistry
|September 2, 1994
Summary
Researchers synthesized novel aza-tricyclic compounds to antagonize substance P (SP) receptors. Compound affinity varied with fused ring size and fusion mode, correlating with steric bulk and substituent dihedral angles.
Area of Science:
- Medicinal Chemistry
- Pharmacology
- Organic Synthesis
Background:
- Substance P (SP) is a neuropeptide implicated in various physiological processes.
- SP antagonists are investigated for potential therapeutic applications.
- Quinuclidine derivatives have shown promise as SP receptor antagonists.
Purpose of the Study:
- To synthesize and characterize novel aza-tricyclic analogs of a known quinuclidine SP antagonist.
- To investigate the structure-activity relationships (SAR) of these new compounds.
- To explore correlations between SP receptor affinity and structural features.
Main Methods:
- Synthesis of a series of aza-tricyclic compounds based on the quinuclidine scaffold.
- Evaluation of SP receptor binding affinity for the synthesized analogs.
- Analysis of structural parameters, including fused ring size, fusion mode, steric bulk, and dihedral angles.
Main Results:
- SP receptor affinity was significantly influenced by the size of the fused ring system.
- The mode of ring fusion to the quinuclidine core also modulated receptor affinity.
- Correlations were identified between receptor affinity and the steric bulk of the fused ring, as well as the dihedral angle of key substituents.
Conclusions:
- Aza-tricyclic analogs of quinuclidine exhibit variable SP receptor affinity.
- Structural modifications, specifically fused ring characteristics and substituent orientation, are critical determinants of antagonist potency.
- These findings provide insights for the rational design of novel SP receptor modulators.