Alfonso Nino * , Camelia Munoz - Caro , Ramon Carbo - Dorca , Xavier Gironesa

26 expresses the activity as a function of the aminopyridine pK , the interaction energy with the receptor, and a quotient a 27 of partition functions. Molecular quantum similarity theory is introduced in the model to express the activity as a 28 function of the principal components of the similarity matrix for a series of agonists. To validate the model, a set of 29 five active (protonated) aminopyridines is considered: 2-aminopyridine, 3-aminopyridine, 4-aminoquinoleine, 430 aminopyridine, and 3,4-diaminopyridine. A regression analysis of the model gives good results for the variation of 31 the observed activity with the overlap similarity index when pyridinic rings are superposed. The results support the 32 validity of the model, and the hypothesis of a ligand–receptor entropy variation depending mainly on the nature of 33 the ligand. In addition, the results suggest that the pyridinic ring must play an active role in the interaction with the 34 receptor site. This interaction with the protonated pyridinic nitrogen can involve a cation–p interaction or a donor 35 hydrogen bond. The amine groups, at different relative positions of the pyridinic nitrogen, can form one or more 36 hydrogen bonds due to the C symmetry of the inner part of the pore in the K channel. q 4 37 2003 Published by Elsevier Science B.V. 38 39