Synthesis and in vitro and in vivo functional studies of ortho-substituted phenylpiperazine and N-substituted 4-N-(o-methoxyphenyl)aminopiperidine analogues of WAY100635

M M Mensonides-Harsema; Y Liao; H Böttcher; G D Bartoszyk; H E Greiner; J Harting; P de Boer; H V Wikström

doi:10.1021/jm991088y

Synthesis and in vitro and in vivo functional studies of ortho-substituted phenylpiperazine and N-substituted 4-N-(o-methoxyphenyl)aminopiperidine analogues of WAY100635

J Med Chem. 2000 Feb 10;43(3):432-9. doi: 10.1021/jm991088y.

Authors

M M Mensonides-Harsema¹, Y Liao, H Böttcher, G D Bartoszyk, H E Greiner, J Harting, P de Boer, H V Wikström

Affiliation

¹ Department of Medicinal Chemistry, University of Groningen, A. Deusinglaan 1, NL-9713 AV Groningen, The Netherlands. m.m.mensonides@farm.rug.nl

PMID: 10669570
DOI: 10.1021/jm991088y

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 Test compounds 12 and 14, in which the arylpiperazine moiety of 2 has been replaced by an arylaminopiperidine moiety, showed no affinity or antagonistic activity at the 5-HT(1A) receptor.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

8-Hydroxy-2-(di-n-propylamino)tetralin
Aminopyridines / chemical synthesis*
Aminopyridines / chemistry
Aminopyridines / metabolism
Aminopyridines / pharmacology
Animals
Frontal Lobe / metabolism
Guinea Pigs
Hypothermia / chemically induced
Ileum / drug effects
Ileum / physiology
In Vitro Techniques
Muscle Contraction / drug effects
Muscle, Smooth / drug effects
Muscle, Smooth / physiology
Piperazines / chemical synthesis*
Piperazines / chemistry*
Piperazines / metabolism
Piperazines / pharmacology
Pyridines / chemistry*
Radioligand Assay
Rats
Receptors, Serotonin / drug effects*
Receptors, Serotonin / metabolism
Receptors, Serotonin, 5-HT1
Serotonin Antagonists / chemical synthesis*
Serotonin Antagonists / chemistry
Serotonin Antagonists / metabolism
Serotonin Antagonists / pharmacology
Serotonin Receptor Agonists
Structure-Activity Relationship
Ultrasonics
Vocalization, Animal / drug effects

Substances

Aminopyridines
N-(2-(4-(2-hydroxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide
Piperazines
Pyridines
Receptors, Serotonin
Receptors, Serotonin, 5-HT1
Serotonin Antagonists
Serotonin Receptor Agonists
N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide
8-Hydroxy-2-(di-n-propylamino)tetralin