Abstract
WAY100635 (2), N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohe xanecarboxamide, is a silent serotonin 5-HT(1A) antagonist, which is now widely used to study the 5-HT(1A) receptor both in vivo and in vitro. In this paper, we describe the synthesis and in vitro (5-HT(1A) affinity and pA(2) values at guinea pig ileum strips) and in vivo (hypothermia and ultrasonic vocalization) pharmacology at the serotonin 5-HT(1A) receptor of several closely related analogues of 2. Test compounds 12 and 14, in which the arylpiperazine moiety of 2 has been replaced by an arylaminopiperidine moiety, showed no affinity or antagonistic activity at the 5-HT(1A) receptor. Substitution of the o-methoxy group of 2 by larger fluoroalkoxy or sulfonyloxy substituents did not alter the in vitro or in vivo pharmacology to any great extent; in vivo both the fluoropropyl analogue 5 and the triflate analogue 7 are equipotent to WAY100635 itself. The O-desmethyl analogue 3 proved to be the most potent antagonist at the serotonin 5-HT(1A) postsynaptic receptor sites in this series.
MeSH terms
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8-Hydroxy-2-(di-n-propylamino)tetralin
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Aminopyridines / chemical synthesis*
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Aminopyridines / chemistry
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Aminopyridines / metabolism
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Aminopyridines / pharmacology
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Animals
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Frontal Lobe / metabolism
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Guinea Pigs
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Hypothermia / chemically induced
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Ileum / drug effects
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Ileum / physiology
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In Vitro Techniques
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Muscle Contraction / drug effects
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Muscle, Smooth / drug effects
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Muscle, Smooth / physiology
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Piperazines / chemical synthesis*
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Piperazines / chemistry*
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Piperazines / metabolism
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Piperazines / pharmacology
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Pyridines / chemistry*
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Radioligand Assay
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Rats
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Receptors, Serotonin / drug effects*
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Receptors, Serotonin / metabolism
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Receptors, Serotonin, 5-HT1
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Serotonin Antagonists / chemical synthesis*
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Serotonin Antagonists / chemistry
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Serotonin Antagonists / metabolism
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Serotonin Antagonists / pharmacology
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Serotonin Receptor Agonists
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Structure-Activity Relationship
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Ultrasonics
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Vocalization, Animal / drug effects
Substances
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Aminopyridines
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N-(2-(4-(2-hydroxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide
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Piperazines
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Pyridines
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Receptors, Serotonin
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Receptors, Serotonin, 5-HT1
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Serotonin Antagonists
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Serotonin Receptor Agonists
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N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide
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8-Hydroxy-2-(di-n-propylamino)tetralin