High-affinity interactions of ligands at recombinant guinea pig 5HT7 receptors.
The serotonin 5HT7 receptor has been implicated in numerous physiological and pathological processes from circadian rhythms to depression and schizophrenia. Clonal cell lines heterologously expressing recombinant receptors offer good models for understanding drug-receptor interactions and development of quantitative structure-activity relationships (QSAR). Comparative Molecular Field Analysis (CoMFA) is an important modern QSAR procedure that relates the steric and electrostatic fields of a set of aligned compounds to affinity. Here, we utilized CoMFA to predict affinity for a number of high-affinity ligands at the recombinant guinea pig 5HT7 receptor. Using R-lisuride as the template, a final CoMFA model was derived using procedures similar to those of our recent papers. The final cross-validated model accounted for >85% of the variance in the compound affinity data, while the final non-cross validated model accounted for >99% of the variance. Model evaluation was done using cross-validation methods with groups of 5 ligands. Twenty cross-validation runs yielded an average predictive r2(q2) of 0.779 +/- 0.015 (range: 0.669-0.867). Furthermore, 3D-chemical database search queries derived from the model yielded hit lists of promising agents with high structural similarity to the template. Together, these results suggest a possible basis for high-affinity drug action at 5HT7 receptors.
Wilcox
R E
RE
College of Pharmacy, University of Texas at Austin, 78712, USA. wilcoxrich@mail.utexas.edu
Ragan
J E
JE
Pearlman
R S
RS
Brusniak
M Y
MY
Eglen
R M
RM
Bonhaus
D W
DW
Tenner
T E
TE
Miller
J D
JD
D000818:Animals; D016466:CHO Cells; D003198:Computer Simulation; D006224:Cricetinae; D015195:Drug Design; D004873:Ergolines / Q000737:chemistry / Q000378:metabolism; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007700:Kinetics; D008024:Ligands; D008958:Models, Molecular; D011487:Protein Conformation; D021281:Quantitative Structure-Activity Relationship; D011985:Receptors, Serotonin / Q000737:chemistry* / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D012702:Serotonin Antagonists / Q000737:chemistry / Q000378:metabolism; D055672:Static Electricity; D013816:Thermodynamics
D004873:Ergolines; D008024:Ligands; D011985:Receptors, Serotonin; D011994:Recombinant Proteins; D012702:Serotonin Antagonists; C104425:serotonin 7 receptor