Synthesis and SAR of analogues of the M1 allosteric agonist TBPB. Part I: Exploration of alternative benzyl and privileged structure moieties

https://doi.org/10.1016/j.bmcl.2008.09.023Get rights and content

Abstract

This Letter describes the first account of the synthesis and SAR, developed through an iterative analogue library approach, of analogues of the highly selective M1 allosteric agonist TBPB. With slight structural changes, mAChR selectivity was maintained, but the degree of partial M1 agonism varied considerably.

Graphical abstract

The synthesis and SAR of analogues of the M1 allosteric agonist TBPB is described. With slight structural changes, mAChR selectivity was maintained, but the degree of partial agonism varied considerably.

  1. Download : Download full-size image

Section snippets

Acknowledgments

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

References and notes (20)

  • C.C. Felder et al.

    J. Med. Chem.

    (2000)
  • N.J.M. Birdsall et al.

    Trends Pharm. Sci.

    (2001)
  • R.A. Eglen et al.

    Trends Pharm. Sci.

    (2001)
    D. Tarsy et al.

    N. Engl. J. Med.

    (2006)
  • A. Fisher

    Jpn. J. Pharmacol.

    (2000)
    A. Caccamo et al.

    Neuron

    (2006)
  • C.J. Langmead et al.

    Mol. Pharm.

    (2006)
  • S. Lazareno et al.

    Mol. Pharm.

    (1998)
  • S. Sharma et al.

    Bioorg. Med. Chem. Lett.

    (2008)
  • T.I. Bonner et al.

    Science

    (1987)
    T.I. Bonner et al.

    Neuron

    (1988)
  • F.P. Bymaster et al.

    Neurochem. Res.

    (2003)
  • R.M. Eglen et al.

    Curr. Opin. Chem. Biol.

    (1999)
There are more references available in the full text version of this article.

Cited by (38)

  • 1-BENZYLSPIRO[PIPERIDINE-4,1′-PYRIDO[3,4-b]indole] ‘co-potentiators’ for minimal function CFTR mutants

    2021, European Journal of Medicinal Chemistry
    Citation Excerpt :

    A synthetic scheme to enable investigation of co-potentiator structure-activity relationships (target analogs 1–6) was devised as outlined in Scheme 1 for the efficient synthesis and modification of the spiro [piperidine-4,1′-pyrido [3,4-b]indole] scaffold (9). Adapting technology developed by Mokrosz [10], commercial tryptamines (8) were condensed with N-alkylated (11 → 12; R2-X in CH2Cl2 + K2CO3) [11,12] piperidin-4-ones (12 where n = 1) to directly deliver the targeted spiro [piperidine-4,1′-pyrido [3,4-b]indole] 9 by a classical Pictet–Spengler reaction [13,14]. However, when preparing R2 analogs of 9, it proved more efficient to prepare unalkylated analog 10 [acetic acid-mediated condensation of tryptamine 8 with piperidin-4-one (11; n = 1)] and then subsequently perform selective N1-alkylation of 10 (R2-X in CH2Cl2 + K2CO3) to give 9.

  • Surface modified nano-lipid drug conjugates of positive allosteric modulators of M1 muscarinic acetylcholine receptor for the treatment of Alzheimer's disease

    2017, Medical Hypotheses
    Citation Excerpt :

    The progression of AD is characterized by Aβ peptide accumulation and hence treatment strategies which reduce the formation and accumulation of Aβ peptide are under investigation [21]. The selective M1 receptor activation not only provides symptomatic relief, but also has disease modifying effects in AD patients by intervening the process undergone by amyloid precursor protein (APP) [22–24]. APP undergoes proteolytic cleavage by two pathways, viz., amyloidogenic and non-amyloidogenic pathways.

  • Molecular mechanisms of bitopic ligand engagement with the M<inf>1</inf> muscarinic acetylcholine receptor

    2014, Journal of Biological Chemistry
    Citation Excerpt :

    This is consistent with previous findings at the M1 and M2 mAChRs and the reported mode of binding of 77-LH-28-1 (10, 15, 22), suggesting a different role for TM2 in bitopic ligand efficacy compared with orthosteric ligands (51). Indeed, previous structure-activity and truncation studies of TBPB (19, 53) have demonstrated that modification or removal of the benzimidazolone moiety of TBPB impairs the agonist activity of the molecule. This appears consistent with the predicted engagement of the moiety of TM2.

  • Allosteric modulation of the M<inf>1</inf> muscarinic acetylcholine receptor: Improving cognition and a potential treatment for schizophrenia and Alzheimer's disease

    2013, Drug Discovery Today
    Citation Excerpt :

    The hallmark of the progression of AD is the formation of amyloid plaques through Aβ accumulation, which has led to the investigation of many potential therapies that inhibit the formation of Aβ peptides (Fig. 2; and see: http://www.alz.org). It has been postulated that increasing M1 receptor activity could not only provide symptomatic relief but also have disease-modifying outcomes in AD patients by influencing the processing of amyloid precursor protein (APP) [47–49]. APP is known to undergo proteolytic cleavage in two competing pathways: amyloidogenic and nonamyloidogenic [50].

  • Allosteric modulators of rhodopsin-like G protein-coupled receptors: Opportunities in drug development

    2012, Pharmacology and Therapeutics
    Citation Excerpt :

    Mutagenesis studies have been performed to identify amino acids in the extracellular loops critical for binding and modulatory function (Chan et al., 2008; Nawaratne et al., 2010). In addition to NAMs and PAMs at mAchRs, allosteric agonists have been identified, such as the potent and highly M1-selective agonists 77-LH-28-1 (15) and TBPB (16) (Bridges et al., 2008; Langmead et al., 2008). Like the PAMs at M1 mAchRs, allosteric M1 agonists such as 15 have potential for the treatment of Alzheimer's disease and schizophrenia.

View all citing articles on Scopus

These authors contributed equally to this work.

View full text