Abstract. Objective and Design: Investigation of the prin- ciples of ligand-receptor interaction in histamine receptors can help to provide a solid foundation for structure-based drug design. Stable isotope labelling of the ligand ‘Hista- mine’ has been performed and 1D 13 C CP MAS and 2D Radio Frequency Dipolar Recoupling (RFDR) spectra for the ligand are presented. Hyperfine signals were well spread and did not suffer from any sizable line broadening. The produc- tion of H 1 receptor for Magic Angle Spinning NMR studies is currently in progress. Treatment: An agonist binding domain is proposed using homology modeling, database searches and mutagenesis data for the H 1 receptor. Methods: Homology modeling, Database searches for Ex- pressed sequence Tag (ESTs), Magic Angle Spinning Nuclear Magnetic Resonance analysis of the ligand histamine. Results: The three-dimensional receptor model and mutage- nesis studies suggest that the amine of the agonist histamine may form an ion pair with the TM III Asp, whereas the imi- dazole ring of histamine may associate with TM V Asp and Thr. Conclusions: Homology modeling studies confirms the absence of TM VIII in the H 1 receptor. According to the mod- el the histamine in particular interacts with the transmem- brane (TM) regions of the H 1 receptor structure, in particular TM helix III and V. This is in line with recent mutagenesis studies. Database search methods for ESTs have been used for electronic prediction of tissue distribution of H 1 receptor expression. The results indicate that the H 1 expression is highest in heart and skeletal muscle, which may be of impor- tance for drug targeting. Key words: Histamine H 1 receptors – G protein coupled receptors – MAS NMR – Ligand binding – ESTs Inflamm. res. 52 (2003) 417 – 423 1023-3830/03/100417-07 DOI 10.1007/s00011-003-1195-3 Introduction The development of selective histamine receptor(s) agonists and antagonists has received considerable attention because of their potential use as pharmacological agents against a variety of human pathologies, including acid-peptic disor- ders, duodenal ulcers, asthma and allergies. Biotechnology using molecular biology, biophysics, and computational approaches provides an alternative approach for classical pharmacological screening to look at ligand-receptor interac- tions and receptor specificity, which should allow to design selective drugs based on detailed structural principles. Cur- rent therapies as described in a standard pharmacology text, for example Goodman & Gilman’s ‘The Pharmacological Basis of Therapeutics’, are based on no more than 500 mole- cular drug targets. These traditional targets reveal what have been the most fruitful paths for therapeutic development in the past, and give a glimpse of where genomic sciences may yield drug-discovery success in the future. The cellular tar- gets of most prescription drugs are proteins and a large pro- portion of these are plasma membrane bound. For the latter class, a drug does not need to enter the cell, but binds to the extracellular binding site of the protein and can control intra- cellular reactions from the outside. These molecular drug tar- gets can be further categorized into biochemical classes such as receptors, enzymes, matrix adhesion factors and ion chan- nels. In this report we will address specific approaches to study function, structure and relevance of a major pharma- ceutical target family, namely G-Protein Coupled Receptors, exemplified in the histamine H 1 receptor. G-Protein Coupled Receptors Biomembranes are based upon a bilayer matrix composed of a mixture of lipid and other amphiphilic molecules creating a thin but crucial separation between the inside and the out- © Birkhäuser Verlag, Basel, 2003 Inflammation Research Analysis of histamine and modeling of ligand-receptor interactions in the histamine H 1 receptor for Magic Angle Spinning NMR studies V. R. Prasad Ratnala 1 , F. B. Hulsbergen 2 , H. J. M. de Groot 1 and W. J. de Grip 1,2 1 Leiden Institute of Chemistry, Gorlaeus Laboratoria, Einsteinweg 55, P.O. Box 9502, 2300 RA Leiden, The Netherlands, Fax: ++ 31 71 5274603, e-mail: r.prasad@fwncism1.leidenuniv.nl 2 Department of Biochemistry UMC-160, Nijmegen Center of Molecular Life Sciences, University Medical Center Nijmegen, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands Received 3 June 2003; accepted by A. Falus 3 June 2003 Correspondence to: V. R. Prasad Ratnala