International Journal of ChemTech Research CODEN( USA): IJCRGG ISSN : 0974-4290 Vol.1, No.4, pp 1386-1392, Oct-Dec 2009 A Density Functional Based Molecular Surface Electrostatic Potentials of Histamine H1-Agonists Fakhr M. Abu-Awwad 1* and Ahmed M. Mkadmh 2 1 Chemistry Department, Islamic University of Gaza, Box 108 – Gaza, Palestine 2 Chemistry Department, Al-Aqsa University, Gaza, Palestine * Corres.author: dr-fakhr@live.com Abstract: A computational analysis of the electrostatic potentials of nine histamine H1 agonists of various structural modifications has been carried out at the density functional B3P86/6-31G** level of theory. It focuses upon the relationships between these potentials and the H1-agonistic activities of the molecules through identifying any common features. Analysis of several statistically based properties of the surface potentials has revealed that H1-Agonism is a linear function with of the potential’s maxima, max , S V , the averages of the positive values on the surface, + - S V , and the average potential over the entire surface, - S V . The statistical parameters for this linearity has been found as R 2 = 0.999, 2 cv R = 0.998, F = 683.200, and standard error = 2.188. The reached correlation has been used to predict the activities of three H1 agonists, where the results revealed correct trend of agonism, if not the numerical values. Keywords: histamine; H1-agonist; surface electrostatic potential; DFT, B3P86 Introduction Histamine belongs to a group of most important biological amines and plays an essential role both in regulation of many physiological functions and in development of a number of serious pathological states. Histamine exerts its effects by activating histamine receptors, of which four subtypes (H1, H2, H3 and H4) are recognized. Specific activation or blockade of these receptor subtypes has led to a tremendous increase in the knowledge of the roles of histamine in physiology and pathology and the mechanisms involved. 1 H1- agonists are drugs that bind to and activate histamine receptors. Such compounds are of importance for fundamental research on the function of H1 receptors in several physiological and pathophysiological conditions. Although, for therapeutic application, potent and specific H1 agonists do not seem to have any role, such compounds are of importance for fundamental research on the function of H1 receptors. The interaction of a histamine H1 agonist with a receptor is a bimolecular recognition process, where each of them is expected to have a key feature promoting their mutual reception. The H1 agonists are all closely related to the histamine structure (1) and some rules have been derived for their H1 activity. Thus an H1 agonist consists of an aromatic system with an unsubstituted nitrogen atom at the position adjacent to an ethylamine side chain. This ethylamine group is preferably a primary amine. Efforts have been made to modify both constituents in order to improve agonistic activity. Modifications in the ethylene side chain of histamine have not revealed interesting H1 agonists. Methylation of the alpha or beta position leads to reduction of H1 activity. 2 Methylation of the amino group of histamine