Subtype-selective N-methyl-D-aspartate receptor antagonists: synthesis and biological evaluation of 1-(arylalkynyl)-4-benzylpiperidines.
A search of our compound library for compounds with structural similarity to ifenprodil (5) and haloperidol (7) followed by in vitro screening revealed that 4-benzyl-1-(4-phenyl-3-butynyl)piperidine (8) was a moderately potent and selective antagonist of the NR1A/2B subtype of NMDA receptors. Substitution on the benzyl group of 8 did not significantly affect NR1A/2B potency, while addition of hydrogen bond donors in the para position of the phenyl group enhanced NR1A/2B potency. Addition of a hydroxyl moiety to the 4-position of the piperidine group slightly reduced NR1A/2B potency while reducing alpha-1 adrenergic and dopamine D2 receptor binding affinities substantially, resulting in improved overall selectivity for NR1A/2B receptors. Finally, the butynyl linker was replaced with propynyl or pentynyl. When the phenyl was para substituted with amine or acetamide groups, the NR1A/2B potency order was butynyl > pentynyl >> propynyl. For the para methanesulfonamide or hydroxyl groups, the order was butynyl approximately propynyl > pentynyl. The hydroxyl propyne (48) and butyne (23) were among the most potent NR1A/2B antagonists from this study. They both potentiated the effects of L-DOPA in the 6-hydroxydopamine-lesioned rat, a model of Parkinson's disease, dosed at 10 mg/kg ip, but 48 was not active at 30 mg/kg po.
Wright
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CoCensys, Inc., 201 Technology Drive, Irvine, California 92618, USA.
Gregory
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Bigge
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Boxer
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Serpa
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Meltzer
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Wise
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Cai
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Hawkinson
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Konkoy
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Whittemore
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Woodward
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Zhou
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D000818:Animals; D000978:Antiparkinson Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D004357:Drug Synergism; D004594:Electrophysiology; D018691:Excitatory Amino Acid Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D066298:In Vitro Techniques; D007980:Levodopa / Q000494:pharmacology; D008297:Male; D009865:Oocytes; D016627:Oxidopamine / Q000633:toxicity; D010636:Phenols / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014982:Xenopus laevis
C120087:4-(3-(4-benzylpiperidin-1-yl)prop-1-ynyl)phenol; C120086:4-benzyl-1-(4-(4-hydroxyphenyl)but-3-ynyl)piperidine; D000978:Antiparkinson Agents; D018691:Excitatory Amino Acid Antagonists; D010636:Phenols; D010880:Piperidines; D018340:Receptors, Adrenergic, alpha-1; D017448:Receptors, Dopamine D2; D016194:Receptors, N-Methyl-D-Aspartate; D007980:Levodopa; D016627:Oxidopamine