Synthesis and affinities for dopamine (D2) and 5-hydroxytryptamine (5-HT2A) receptors of 1-(benzoylpropyl)-4-(1-oxocycloalkyl-2-ethyl)-piperazines as cyclic butyrophenone derivatives.
Starting from benzo- or thienocycloalkaneacetic acids, we have prepared a series of 1-(3-p-fluorobenzoylpropyl)-4-(1-oxo-benzo- or thienocycloalkyl-2-ethyl)piperazines 8a-e containing both semirigid and linear butyrophenones pharmacophores. The affinities of these compounds for dopamine (D2) and 5-hydroxytryptamine (5-HT2A) receptors were evaluated in vitro in receptor-binding assays and in functional experiments. The ratios of pKi's for 5-HT2A/D2 receptors may be useful for rapid screening of new compounds and assessing potential induction of extrapyramidal symptoms; ratio values > or = 1.12 (Meltzer's ratio) are predictive of an atypical antipsychotic profile. The new molecules had a ratio in the range of 0.96-1.11 while haloperidol showed a ratio of 0.93. The 2-piperazinoethyl thiotetralone derivative 8d (QF 0506B) with a ratio of 1.11 was the most active compound.
Raviña
E
E
Department of Organic Chemistry, University of Santiago de Compostela, Spain.
Fueyo
J
J
Masaguer
C F
CF
Negreira
J
J
Cid
J
J
Loza
I
I
Honrubia
A
A
Tristán
H
H
G-Ferreiro
T
T
Fontenla
J A
JA
Rosa
E
E
Calleja
J M
JM
De Ceballos
M L
ML
D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D002090:Butyrophenones; D015259:Dopamine Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D010879:Piperazines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000187:drug effects*; D011985:Receptors, Serotonin / Q000187:drug effects*; D018490:Serotonin Agents / Q000138:chemical synthesis* / Q000494:pharmacology
D014150:Antipsychotic Agents; D002090:Butyrophenones; D015259:Dopamine Agents; D010879:Piperazines; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin; D018490:Serotonin Agents