Investigations of amide bond variation and biaryl modification in analogues of α7 nAChR agonist SEN12333

• We examine the effect of amide bond connectivity and tetrazole substitution within α7 nAChR agonist SEN12333.
• We examine the effect of biaryl modification of SEN12333, specifically the incorporation of a biphenyl motif.
• The amide bond connectivity of SEN12333 can be reversed while still maintaining potency and agonist activity at α7 nAChRs.
• The pyridine nitrogen is not essential for binding affinity or agonist activity.
• The incorporation of a tetrazole functionality is detrimental for binding affinity and agonist activity.

Several lines of experimental evidence support the involvement of the α7 nAChR in schizophrenia and Alzheimer's disease. Modulators of the α7 nAChR have been extensively reviewed for the treatment of the cognitive deficits associated with these pathologies. SEN12333 represents a novel α7 nAChR agonist chemotype with potential for reduced side effects but requiring further SAR exploration. The present work investigates the amide bond of SEN12333, specifically its connectivity and replacement with the tetrazole functionality, a known cis amide isostere. The results reveal the original amide bond connectivity of SEN12333 to be favorable for binding affinity and agonist activity at α7 nAChRs. The use of a tetrazole isostere completely abolishes affinity and functional activity and suggests that SEN12333 binds in a linear conformation. Results reported herein also suggest the pyridine nitrogen within the terminal aromatic ring of SEN12333 is not essential for binding affinity or functional activity. Further SAR investigations involving manipulation of other moieties contained within SEN12333 are warranted.

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