Struktur‐Wirkung‐Beziehungen ZNS‐aktiver Substanzen, 21. Mitt. 1) : Zwei Derivate von 1‐( o ‐Methoxyphenyl)piperazin mit entgegengesetzter Wirkung auf 5‐HT 1A Rezeptoren

It is intriguing that all postsynaptic 5‐HT 1A receptor antagonists which belong to the 1‐arylpiperazine class of ligands have a 1‐( o ‐methoxyphenyl)‐piperazine fragment or its structural equivalent ( e.g. benzodioxane moiety) in their structure 2–5) . One of them, NAN‐190 ( 1 ) may be regarded as a classic postsynaptic 5‐HT 1A antagonist whose pharmacological and biochemical profiles have been well recognized 2,6,7) . Moreover, regarding all the known 5‐HT 1A antagonists, systematic structure‐activity studies have been conducted for NAN‐190 only, as yet 2,5,8,9) . Recently we showed that the simplification of the amide portion in NAN‐190 ( 1 ) did not change its in vivo profile; moreover, MM‐77 ( 2 ) also appeared to be a potent postsynaptic antagonist of 5‐HT 1A receptors 5) . Even more dramatic structure simplification ( of . 3 vs. 1 ) did not abolish the antagonistic properties of 3 . According to Glennon and coworkers, compound 3 behaved like a weak postsynaptic 5‐HT 1A antagonist in some biochemical tests 8.9) . By contrast, replacement of the 1‐( o ‐methoxyphenyl)piperazine fragment in NAN‐190 by a bridged 1‐phenylpiperazine ring system resulted in analog 5 , which was completely inactive in the in vivo models used 5) .