Synthesis and SAR of analogs of the M1 allosteric agonist TBPB. Part II: Amides, sulfonamides and ureas—The effect of capping the distal basic piperidine nitrogen

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Abstract

This letter describes the further synthesis and SAR, developed through an iterative analog library approach, of analogs of the highly selective M1 allosteric agonist TBPB by deletion of the distal basic piperidine nitrogen by the formation of amides, sulfonamides and ureas. Despite the large change in basicity and topology, M1 selectivity was maintained.

Graphical abstract

This letter describes the further synthesis and SAR, developed through an iterative analog library approach, of analogs of the highly selective M1 allosteric agonist TBPB by deletion of the distal basic piperidine nitrogen by the formation of amides, sulfonamides and ureas. Despite the large change in basicity and topology, M1 selectivity was maintained.

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Acknowledgments

The authors thank the NIH and NIMH for support of our programs (1RO1MH082867-01). The authors specifically acknowledge the support of the Alzheimer’s Association (IIRG-07-57131). T.M.B. acknowledges an ITTD (T90-DA022873) pre-doctoral training grant. N.R.M. acknowledges Ion Channel and Transporter Biology (T32-NS07491) pre-doctoral training grant, and A.E.B. is supported by a National Research Service Award (1FM32 MH079678-01).

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These authors contributed equally to this work.

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