The Neonicotinoid Electronegative Pharmacophore Plays the Crucial Role in the High Affinity and Selectivity for the Drosophila Nicotinic Receptor: An Anomaly for the Nicotinoid Cation-src=

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• 作者：Motohiro Tomizawa ; Nanjing Zhang ; Kathleen A. Durkin ; Marilyn M. Olmstead ; and John E. Casida
• 刊名：Biochemistry
• 出版年：2003
• 出版时间：July 1, 2003
• 年：2003
• 卷：42
• 期：25
• 页码：7819 - 7827
• 全文大小：253K
• 年卷期：v.42,no.25(July 1, 2003)
• ISSN：1520-4995

文摘

Cation-SRC="/images/gifchars/pi.gif" BORDER=0 > interaction, a prominent feature in agonist recognition by neurotransmitter-gatedion channels, does not apply to the anomalous action of neonicotinoids at the insect nicotinic acetylcholinereceptor (nAChR). Insect-selective neonicotinoids have an electronegative pharmacophore (tip) in placeof the ammonium or iminium cation of the vertebrate-selective nicotinoids, suggesting topologicaldivergence of the agonist-binding sites in insect and vertebrate nAChRs. This study defines the molecularand electronic basis for the potent and selective interaction of the neonicotinoid electronegativepharmacophore with a unique subsite of the Drosophila but not of the vertebrate s/gifchars/alpha.gif" BORDER=0>4s/gifchars/beta2.gif" BORDER=0 ALIGN="middle">2 nAChR. Targetsite potency and selectivity are retained when the usual neonicotinoid N-nitroimine (=NNO₂) electronegativetip is replaced with N-nitrosoimine (=NNO) or N-(trifluoroacetyl)imine (=NCOCF₃) in combination withan imidazolidine, imidazoline, thiazolidine, or thiazoline heterocycle. X-ray crystallography establishescoplanarity between the heterocyclic and imine planes, including the electronegative substituent in thetrans configuration. The functional tip is the coplanar oxygen atom of the N-nitrosoimine or the equivalentoxygen of the N-nitroimine. Quantum mechanics in the gas and aqueous phases fully support the conservedcoplanarity and projection of the strongly electronegative tip. Further, a bicyclic analogue with a nitro tipin the cis configuration but retaining coplanarity has a high potency, whereas the N-trifluoromethanesulfonylimine (=NSO₂CF₃) moiety lacking coplanarity confers very low activity. The coplanar systembetween the electronegative tip and guanidine-amidine moiety extends the conjugation and facilitatesnegative charge (s/gifchars/delta.gif" BORDER=0 >^-) flow toward the tip, thereby enhancing interaction with the proposed cationic subsitesuch as lysine or arginine in the Drosophila nAChR.