Synthesis and in vitro and in vivo functional studies of ortho-substituted phenylpiperazine and N-substituted 4-N-(o-methoxyphenyl)aminopiperidine analogues of WAY100635.
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 Test compounds 12 and 14, in which the arylpiperazine moiety of 2 has been replaced by an arylaminopiperidine moiety, showed no affinity or antagonistic activity at the 5-HT(1A) receptor.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.
Mensonides-Harsema
M M
MM
Department of Medicinal Chemistry, University of Groningen, A. Deusinglaan 1, NL-9713 AV Groningen, The Netherlands. m.m.mensonides@farm.rug.nl
Liao
Y
Y
Böttcher
H
H
Bartoszyk
G D
GD
Greiner
H E
HE
Harting
J
J
de Boer
P
P
Wikström
H V
HV
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000631:Aminopyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D005625:Frontal Lobe / Q000378:metabolism; D006168:Guinea Pigs; D007035:Hypothermia / Q000139:chemically induced; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011725:Pyridines / Q000737:chemistry*; D011869:Radioligand Assay; D051381:Rats; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D017366:Serotonin Receptor Agonists; D013329:Structure-Activity Relationship; D014465:Ultrasonics; D014828:Vocalization, Animal / Q000187:drug effects
D000631:Aminopyridines; C404927:N-(2-(4-(2-hydroxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D010879:Piperazines; D011725:Pyridines; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin