3D QSAR studies of 1,3,4-benzotriazepine derivatives as CCK 2 receptor antagonists Kirandeep Kaur, Tanaji T. Talele * Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John’s University, Jamaica, NY 11439, United States 1. Introduction Cholecystokinin (CCK), gastrin, and related peptides include a family of peptide hormones and neuropeptides which exert a variety of physiological actions on the gastrointestinal tract and the central nervous system (CNS) [1,2]. Although both CCK and gastrin share an identical carboxyl-terminal pentapeptide sequence they differ in selectivity for the two known CCK receptor subtypes, the CCK 1 (CCK 1 R) and the CCK 2 (CCK 2 R) receptors as a result of tyrosine sulfation at the seventh position (CCK) or at the sixth position (gastrin) from the carboxyl terminus. Furthermore, while both receptors recognize sulfated CCK with comparable high affinity, the CCK 2 R has high affinity for both sulfated and non- sulfated gastrin [3,4]. CCK 1 R and CCK 2 R are seven-transmembrane spanning recep- tors that belong to the superfamily of G-protein-coupled receptors (GPCR’s) and have 50% homology [5–7]. The gastrointestinal polypeptide hormone gastrin has been known to stimulate gastric acid secretion and gastrointestinal cell growth in peripheral tissues. Hence, efforts have been made to develop agents that inhibit gastrin activity especially on gastric secretion, by acting as CCK 2 R antagonists [8]. These compounds have been found to be beneficial in the treatment of gastric acid-related disorders, such as gastro esophageal reflux disease (GERD), proton pump inhibitor (PPI)-evoked rebound acid hypersecretion [9], and in certain types of cancer [10–12]. Furthermore, since activation of CCK 2 R in the CNS by CCK led to the mediation of pain, panic, and anxiety, it is also possible that CCK 2 antagonists may have a role in controlling these disorders [13,14]. Prominent actions mediated by CCK 2 R’s within the digestive tract include stimulation of acid secretion from gastric parietal cells [15,16], the release of histamine from enterochro- maffin-like cells [17], and the regulation of gut motor functions [18,19]. The development of selective CCK 2 R antagonists encompassing a diverse range of chemical structures have been accomplished by one of two main approaches [20]. The peptoid-based compound (CI-988) [21] and the indole derivative (JB93182) [22] are the most significant examples to stem from using the native peptide hormone as the starting point but, unfortunately, these com- pounds exhibited low oral potency. Initial efforts aimed at creating chiral 1,4- and 1,5-benzodiazepine-based CCK 2 antagonists led to Journal of Molecular Graphics and Modelling 27 (2008) 409–420 ARTICLE INFO Article history: Received 14 February 2008 Received in revised form 15 July 2008 Accepted 19 July 2008 Available online 30 July 2008 Keywords: 3D QSAR CoMFA CoMSIA HQSAR CCK 2 receptor 1,3,4-Benzotriazepine ABSTRACT A number of CCK 2 antagonists have been reported to play an important role in controlling gastric acid- related conditions, nervous system related disorders and certain types of cancer. To obtain the helpful information for designing potent antagonists with novel structures and to investigate the quantitative structure–activity relationship of a group of 62 different CCK 2 receptor antagonists with varying structures and potencies, CoMFA, CoMSIA, and HQSAR studies were carried out on a series of 1,3,4- benzotriazepine-based CCK 2 receptor antagonists. QSAR models were derived from a training set of 49 compounds. By applying leave-one-out (LOO) cross-validation study, cross-validated (r 2 cv ) values of 0.673 and 0.608 and non-cross-validated (r 2 ncv ) values of 0.966 and 0.969 were obtained for the CoMFA and CoMSIA models, respectively. The predictive ability of the CoMFA and CoMSIA models was determined using a test set of 13 compounds, which gave predictive correlation coefficients (r 2 pred ) of 0.793 and 0.786, respectively. HQSAR was also carried out as a complementary study, and the best HQSAR model was generated using atoms, bonds, hydrogen atoms, and chirality as fragment distinction with fragment size (2–5) and six components showing r 2 cv and r 2 ncv values of 0.744 and 0.918, respectively. CoMFA steric and electrostatic, CoMSIA hydrophobic and hydrogen bond acceptor fields, and HQSAR atomic contribution maps were used to analyze the structural features of the datasets that govern their antagonistic potency. ß 2008 Elsevier Inc. All rights reserved. * Corresponding author. E-mail address: talelet@stjohns.edu (T.T. Talele). Contents lists available at ScienceDirect Journal of Molecular Graphics and Modelling journal homepage: www.elsevier.com/locate/JMGM 1093-3263/$ – see front matter ß 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.jmgm.2008.07.003