Binding of nicotine and homoazanicotine analogues at neuronal nicotinic acetylcholinergic (nACh) receptors

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Abstract

A total of 20 substituted analogues of nicotine (1a) and homoazanicotine (3a) were examined in order to determine whether or not they might bind in a similar manner at α4β2 nicotinic acetylcholinergic (nACh) receptors. It was found that parallel structural changes in the two series resulted in parallel shifts in affinity. Evidence suggests that the two series are binding in a comparable fashion.

A series of homoazanicotine derivatives 3 was found to bind at α4β2 nACh receptors in a manner that appears to parallel that of their corresponding racemic nicotine counterparts.

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Acknowledgements

This work was supported in part by DA 05274 and by funding from MURST Cofinanziamento (Rome).

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Cited by (12)

  • Medicinal Chemistry of α4β2 Nicotinic Cholinergic Receptor Ligands

    2004, Progress in Medicinal Chemistry
    Citation Excerpt :

    For example, the affinities of anabasine (7) (R=H; Ki=210 nM) [33], N-methylanabasine (7) (R=Me; Ki=180 nM) [33], cotinine (8) (Ki>100,000 nM) [37], N1,N1′-dimethylnicotinium (Ki>10,000 nM) [26], and myosmine (30) (Ki=3,300 nM) [66] were well below that of nicotine. However, trans-metanicotine (31b) (Ki=26 nM; Table 2.2), also known as RJR-2403, TC-2403, or simply as ‘metanicotine’, binds with higher affinity [67]. The structural requirements for the binding of (31b) at nACh receptors were rather strict and modifications diminished its affinity (Table 2.2).

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