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 [1] 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 [2, 3, 4] 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.     

PRESENTATIONS: FROM KAC-MOODY GROUPS TO PROFINITE AND BACK

We go back and forth between, on the one hand, presentations of arithmetic and Kac-Moody groups and, on the other hand, presentations of profinite groups, deducing along the way new results on both.     

Embeddings of SL(2; ?) into the cremona group

Geometric and dynamic properties of embeddings of SL(2; ℤ) into the Cremona group are studied. Infinitely many nonconjugate embeddings that preserve the type (i.e., that send elliptic, parabolic and hyperbolic elements onto elements of the same type) are provided. The existence of infinitely many nonconjugate elliptic, parabolic and hyperbolic embeddings is also shown. In particular, a group G of automorphisms of a smooth surface S obtained by blowing up 10 points of the complex projective plane is given. The group G is isomorphic to SL(2; ℤ), preserves an elliptic curve and all its elements of infinite order are hyperbolic.