Structure-activity relationships for nicotine analogs comparing competition for [3H]nicotine binding and psychotropic potency

Wang, David X.; Booth, Heather; Lerner-Marmarosh, Nicole; Osdene, T. S.; Abood, Leo G.

doi:10.1002/(sici)1098-2299(199809)45:1<10::aid-ddr2>3.0.co;2-g

Cited by 28 publications

(21 citation statements)

References 15 publications

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“…Our data for 29-methylnicotine binding to rat brain a4b2 receptors was consistent with the data of Wang et al (1998) for racemic 29-methylnicotine, taking into consideration that our 29-methyl-(S)-nicotine has a much higher (.40fold) binding affinity than 29-methyl-(R)-nicotine (Kem, unpublished results).…”

Section: Resultssupporting

confidence: 88%

“…The binding K i values for rat and human a4b2 receptors were also increased .2000-fold and .700-fold, respectively (Table 4). Previous radioligand binding studies also indicated that methylation at this position had detrimental effects on nicotine binding affinity for rat brain high-affinity (a4b2) receptors and that the binding K i of trans-59-methylnicotine was less affected than that of the cis-form (Lin et al, 1994;Wang et al, 1998).…”

Section: Resultsmentioning

confidence: 97%

“…The actions of a few alkylated nicotines on isolated tissues and organs have been reported (Glassco et al, 1994;Dukat et al, 1996). Two laboratories reported extensive rat brain nAChR (later shown to be largely a42b) binding data on the effect of individual methyl substitutions at four of the eight hydrogens on the pyrrolidinium ring (Lin et al, 1994;Kim et al, 1996;Wang et al, 1998). In this paper, we report a comprehensive functional and radioligand binding analysis of all the possible chiral nicotine analogs generated by methyl replacement of each H atom attached to the pyrrolidinium ring of (S)-nicotine for a7 as well as a4b2 nAChRs.…”

Section: Introductionmentioning

confidence: 86%

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A Methyl Scan of the Pyrrolidinium Ring of Nicotine Reveals Significant Differences in Its Interactions with α7 and α4β2 Nicotinic Acetylcholine Receptors

et al. 2020

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The two major nicotinic acetylcholine receptors (nAChRs) in the brain are the a4b2 and a7 subtypes. A "methyl scan" of the pyrrolidinium ring was used to detect differences in nicotine's interactions with these two receptors. Each methylnicotine was investigated using voltage-clamp and radioligand binding techniques. Methylation at each ring carbon elicited unique changes in nicotine's receptor interactions. Replacing the 19-N-methyl with an ethyl group or adding a second 19-N-methyl group significantly reduced interaction with a4b2 but not a7 receptors. The 29-methylation uniquely enhanced binding and agonist potency at a7 receptors. Although 39-and 59-trans-methylations were much better tolerated by a7 receptors than a4b2 receptors, 49-methylation decreased potency and efficacy at a7 receptors much more than at a4b2 receptors. Whereas cis-59-methylnicotine lacked agonist activity and displayed a low affinity at both receptors, trans-59-methylnicotine retained considerable a7 receptor activity. Differences between the two 59-methylated analogs of the potent pyridyl oxymethylene-bridged nicotine analog A84543 were consistent with what was found for the 59-methylnicotines. Computer docking of the methylnicotines to the Lymnaea acetylcholine binding protein crystal structure containing two persistent waters predicted most of the changes in receptor affinity that were observed with methylation, particularly the lower affinities of the cis-methylnicotines. The much smaller effects of 19-, 39-, and 59-methylations and the greater effects of 29and 49-methylations on nicotine a7 nAChR interaction might be exploited for the design of new drugs based on the nicotine scaffold. SIGNIFICANCE STATEMENTUsing a comprehensive "methyl scan" approach, we show that the orthosteric binding sites for acetylcholine and nicotine in the two major brain nicotinic acetylcholine receptors interact differently with the pyrrolidinium ring of nicotine, and we suggest reasons for the higher affinity of nicotine for the heteromeric receptor. Potential sites for nicotine structure modification were identified that may be useful in the design of new drugs targeting these receptors.The views presented in this article are those of the authors and do not necessarily reflect those of the US Food and Drug Administration. No official endorsement is intended nor should be inferred.

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Section: Resultssupporting

confidence: 88%

Section: Resultsmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 86%

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A Methyl Scan of the Pyrrolidinium Ring of Nicotine Reveals Significant Differences in Its Interactions with α7 and α4β2 Nicotinic Acetylcholine Receptors

et al. 2020

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“…1, to acetylcholine receptors. 7 This coupled with studies into the psychotropic potency, 8 potential CNS-focused leads in drugdiscovery 9 and antibacterial activity 10 demonstrates that azetidine derivatives are attractive biologically active motifs.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of azetidines and pyrrolidines via iodocyclisation of homoallyl amines and exploration of activity in a zebrafish embryo assay

et al. 2013

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Room temperature iodocyclisation of homoallylamines stereoselectively delivers functionalised 2-(iodomethyl)azetidine derivatives in high yield. Increasing reaction temperature from 20 °C to 50 °C switches the reaction outcome to realise the stereoselective formation of functionalised 3-iodopyrrolidine derivatives. It was shown that these pyrrolidines are formed via thermal isomerisation of the aforementioned azetidines. Primary and secondary amines could be reacted with iodomethyl azetidine derivatives to deliver stable methylamino azetidine derivatives. With subtle changes to the reaction sequences homoallyl amines could be stereoselectively converted to either cis- or trans-substituted 3-amino pyrrolidine derivatives at will. The stereochemical divergent synthesis of cis and trans substituted pyrrolidines supports an ion part, aziridinium, isomerisation pathway for azetidine to pyrrolidine isomerisation. Six azetidine derivatives were probed in a zebrafish embryo developmental assay to detect potential biological effects through the analysis of morphology and motility behaviour phenotypes. The range of effects across the probed molecules demonstrates the suitability of this assay for screening azetidine derivatives. One of the probed molecules, rac-(((cis)-1-benzyl-4-phenylazetidin-2-yl)methyl)piperidine, exhibited particularly interesting effects in the developmental assay presenting with hypopigmentation and reduced circulation amongst others. This shows that the zebrafish embryo provides a fast, sensitive and effective way to screen new compounds and in the future in combination with existing in vivo and in vitro assays it will become an integral part in drug discovery and development.

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“…The four-member ring analogue, N -methyl-(3-pyridyl)azetidine ( 4 ), produced a 10-fold increase in binding affinity compared with nicotine [6]. Wang et al demonstrated that 6-methylnicotine ( 5 ) possess higher affinity in competition studies for [3H]nicotine in rat brain membranes [7]. Anabasine 6 has been established to be a selective α7-nAChR agonist in an animal model and with low toxicity for the potential treatment of schizophrenia [1e].…”

Section: Introductionmentioning

confidence: 99%

A new and efficient approach to the synthesis of nicotine and anabasine analogues

Huang

Ortiz-Marciales

Jesús

et al. 2009

Journal of Heterocyclic Chem

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A straightforward and practical approach was established for the synthesis of nicotine and anabasine analogues by the cyclization of mesylated 1-(3-pyridinyl)-1,4, and 1,5-diol derivatives to form the pyrrolidino or piperidino fragments. Nicotine analogue (S)-15 was prepared with good enantioselectivity using the developed azacyclization procedure of nonracemic (R)-1-pyridin-3-yl-butane-1,4-diol, which was obtained by the borane-mediated reduction of ketone 12 in the presence of the spiroborate ester derived from diphenyl prolinol and ethylene glycol.

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Structure-activity relationships for nicotine analogs comparing competition for [3H]nicotine binding and psychotropic potency

Cited by 28 publications

References 15 publications

A Methyl Scan of the Pyrrolidinium Ring of Nicotine Reveals Significant Differences in Its Interactions with α7 and α4β2 Nicotinic Acetylcholine Receptors

A Methyl Scan of the Pyrrolidinium Ring of Nicotine Reveals Significant Differences in Its Interactions with α7 and α4β2 Nicotinic Acetylcholine Receptors

Synthesis of azetidines and pyrrolidines via iodocyclisation of homoallyl amines and exploration of activity in a zebrafish embryo assay

A new and efficient approach to the synthesis of nicotine and anabasine analogues

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