Synthesis and in Vitro and in Vivo Functional Studies of Ortho-Substituted Phenylpiperazine and N-Substituted 4-N-(o-Methoxyphenyl)aminopiperidine Analogues of WAY100635

• Published in: Journal of medicinal chemistry 2000-02, Vol.43 (3), p.432-439
• Main Authors: Mensonides-Harsema, Marguérite M, Liao, Yi, Böttcher, Henning, Bartoszyk, Gerd D, Greiner, Hartmunt E, Harting, Jürgen, de Boer, Peter, Wikström, Håkan V
• Format: Article
• Language: English
• Subjects: 8-Hydroxy-2-(di-n-propylamino)tetralin; Aminopyridines - chemical synthesis; Aminopyridines - chemistry; Aminopyridines - metabolism; Aminopyridines - pharmacology; Animals; Biological and medical sciences; Frontal Lobe - metabolism; Guinea Pigs; Hypothermia - chemically induced; Ileum - drug effects; Ileum - physiology; In Vitro Techniques; Medical sciences; Muscle Contraction - drug effects; Muscle, Smooth - drug effects; Muscle, Smooth - physiology; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; 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; Serotoninergic system; Structure-Activity Relationship; Ultrasonics; Vocalization, Animal - drug effects
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm991088y

WAY100635 (2), N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide, is a silent serotonin 5-HT1A antagonist, which is now widely used to study the 5-HT1A receptor both in vivo and in vitro. In this paper, we describe the synthesis and in vitro (5-HT1A affinity and pA 2 values at guinea pig ileum strips) and in vivo (hypothermia and ultrasonic vocalization) pharmacology at the serotonin 5-HT1A 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 Test compounds 12 and 14, in which the arylpiperazine moiety of 2 has been replaced by an arylaminopiperidine moiety, showed no affinity or antagonistic activity at the 5-HT1A receptor.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-HT1A postsynaptic receptor sites in this series.