QSAR of Adenosine Receptor Antagonists II: Exploring Physicochemical Requirements for Selective Binding of 2-Arylpyrazolo[3,4-c]quinoline Derivatives with Adenosine A 1 and A 3 Receptor Subtypes Kunal Roy Drug Theoretics and Cheminformatics Lab, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, Jadavpur University, Calcutta 700 032, India; e-mail: kunalroy_in@yahoo.com; URL: http://www.geocities.com/kunalroy_in Abstract Considering potential of selective adenosine receptor subtype ligands in the development of prospective drug candidates, A 1 and A 3 receptor binding affinity data of 2- arylpyrazolo[3,4-c]quinoline derivatives have been sub- jected to QSAR analyses to explore the physicochemical requirements for selective binding. The study has been carried out with Wang-Ford charges of the common atoms of the molecules calculated from their energy minimized conformations using AM1 technique. Apart from the charge parameters, physicochemical variables like parti- tion coefficient and molar refractivity of the whole molecules have been used along with suitable indicator variables. The study shows that substituents on the appended 2-phenyl ring and 4-amino or 4-keto substitution on the pyrazolo[3,4-c]quinoline nucleus modulate the selectivity pattern. Further, negative charge on the quino- line nitrogen and volume and lipophilicity of the whole molecules are important contributors to the selectivity. 1 Introduction Adenosine receptors (AR) represent one of the promising drug targets of contemporary interest. As nearly all cells express specific adenosine receptors, adenosine serves as important physiological regulator and acts as cardioprotec- tor, neuroprotector, chemoprotector and immunomodula- tor [1 ± 4]. There exist a large number of ligands that have been generated by introducing several modifications in the structure of the lead compounds. Based on pharmacological studies and molecular cloning, four different subtypes (A 1 , A 2A ,A 2B and A 3 ) of G-protein coupled adenosine receptors have been identified [2]. New genetic and epigenetic tools, such as antisense and gene -knockin× and -knockout× techniques, have been used for elucidation of the functions of these receptors [5]. It has been reported that somnogenic effect of adenosine inthebasalforebrainareamaybemediatedbyA 1 receptors anditsexpressionmightberegulatedbyinductionofNF-kB proteinastranscriptionfactor[6].SelectiveA 1 agonistshave high neuroprotective actions [7]. A 2A receptor is thought to play a role in a number of physiological responses and pathological conditions. An- tagonistic interactions between A 2A receptors and dopa- mine D 2 receptors have been described. A 2A receptor antagonists may be useful for treatment of neurodegener- ative disorders such as Parkinson×s disease while A 2A agonists may treat certain types of sleep disorders [8 ± 13]. A 2A receptor desensitizes A 1 receptor and reduces A 1 mediated effects [14]. A 2A receptor has been identified as novel target in renal diseases [12]. The knowledge of A 2B receptors lags behind that of other receptor types. A 2B receptors have been implicated in the regulation of vascular smooth muscle tone, cell growth, intestinal function and neurosecretion. The role of A 2B receptors in mast cell activation and the potential relevance of this action on asthma have also been reviewed [15]. Activation of A 3 receptors has been shown to stimulate phospholipase C and D and to inhibit adenylate cyclase. It also causes release of inflammatory mediators like hista- mine from mast cells leading to inflammation and hypo- tension.HighlyselectiveA 3 antagonistshavebeenindicated as potential drug for the treatment of asthma and inflam- mation while agonists have been shown to possess cardio- protective action [1, 2]. Potent and selective A 1 and A 3 ligands have been developed. However, potent and selective A 2A and A 2B 614 QSAR Comb. Sci. 22 (2003) DOI: 10.1002/qsar.200330821 ¹ WILEY-VCH Verlag GmbH&Co. KGaA, Weinheim 1611-020X/03/0607-0614 Key words: QSAR, AM1 calculations, adenosine receptor ligands, 2-arylpyrazolo[3,4-c]quinoline derivates Kunal Roy & Combinatorial Science