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Predict receptor occupancy for compound A at receptor R2 based on its occupancy at receptor R1
Author(s) -
Mu S.,
Mitchell S.,
Ebling W.
Publication year - 2005
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2004.12.057
Subject(s) - receptor , occupancy , chemistry , binding site , biophysics , pharmacology , biochemistry , biology , ecology
Purpose To illustrate a new method for calculating receptor occupancy (RO) for compound (A) that binds to two receptors R1 and R2. Methods Compound A is a competitive inhibitor for an endogenous brain chemical S at two functionally distinct receptors R1 and R2 in the central neural system. The receptor occupancy can be quantitated through neuro‐imaging for R1, but not for R2. Analytical solution of RO at R2 at given RO at R1 was derived as a function of binding affinities of A and S to both receptors, and concentration of S at the site of action. Major assumptions in the derivation include: fraction of radiotracer that binds to R2 is negligible; stoichiometry of binding between A and receptors R1 and R2, and between S and R1 and R2, respectively, is 1:1; S is the only significant competitor with A for both receptors. RO at R2 was generated under 3 binding affinity scenarios: a) A binds to R1 and R2 equally; b) A binds R1> R2; c) A binds R2>R1. Results Exposure‐RO relationships were generated which allowed evaluation under different scenarios. The robustness of the assumptions was also tested. Conclusion This method allows the estimation of RO for a receptor conditional on RO information at another receptor. Simulated exposure‐RO relationship helps dose selection for compound A that maximizes its occupancy at both receptors while avoiding undesirable effects. Clinical Pharmacology & Therapeutics (2005) 77 , P43–P43; doi: 10.1016/j.clpt.2004.12.057