Allosteric modulators of α7 neuronal nicotinic acetylcholine receptors (nAChRs) are a promising, alternative approach to the treatment of neurodegenerative diseases. Previously we reported that meta-chlorophenylguanidine (mCPG; 1) and its N-methyl analog 2, developed in our laboratory, exert negative allosteric modulator (NAM) actions at α7 nAChRs. To determine their plausible binding site and modes, homology models of the extracellular domain (ECD; PDB ID: 3SQ9) and the transmembrane domain (TM; PDB ID: 2LLY) of hα7 nAChRs were generated (Modeller 9.12). Through alignment of amino acid sequences and available mutagenesis data, we identified three key amino acid residues (i.e., Thr221 from ECD, and Met276, Thr473 from TM) that might form an essential interaction with arylguanidines. HINT (Hydropathic INTeractions) analyses indicated an energetic preference (the larger the number the more energetically preferable) for the interaction of 1 and 2 at the ECD (HINT score: 917 and 627, respectively) allosteric site over the TM domain (129 and 273, respectively) site. Docking studies resulted in different binding modes for 1 and 2. Thus, two series of analogs (n = 16) with parallel substituent modifications at the aryl 3-position were synthesized and evaluated for functional activity in two-electrode voltage clamp assays using frog oocyte-expressing α7 nAChRs (IC50 value range = 21 – 118 μM; 12 – 125 μM, respectively). A poor correlation (r = 0.474; n = 8) of pIC50 values of the 1 series versus pIC50 values of the 2 series supported our docking results. Hansch-type QSAR studies on the 2 series showed a significant correlation with the minimum width (Verloop B1) (r = 0.927; n = 8) and lipophilic nature (π) (r = 0.912; n = 8) of the 3-position substituent. However, a significant internal correlation exists between the two properties (r = 0.956; n = 8). HINT-based hydropathic maps are in agreement with biological data. [ARDRAF]

Arylguanidine NAMs for α7 nAChRs: Where do they bind and why?

249th National Meeting (2015)

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