Synthesis and structure-activity relationships of a new model of arylpiperazines. 1. 2-[[4-(o-methoxyphenyl)piperazin-1-yl]methyl]-1, 3-dioxoperhydroimidazo[1,5-alpha]pyridine: a selective 5-HT1A receptor agonist.
A series of new bicyclohydantoin-arylpiperazines was prepared and evaluated for affinity at 5-HT1A, alpha 1, and D2 receptors. Most of the compounds showed very low affinity for D2 receptors, and most of them demonstrated moderate to high affinity for 5-HT1A and alpha 1 receptor binding sites. SAR observations indicated that the length of the alkyl chain between the arylpiperazine and the hydantoin moiety is of great importance for 5-HT1A/alpha 1 affinity and selectivity, n = 1 being the optimal value. Compound 1h, 2-[[4-(o-methoxyphenyl)piperazin-1-yl] methyl]-1,3-dioxoperhydroimidazo [1,5-alpha]pyridine, bound at 5-HT1A sites with nanomolar affinity (Ki = 31.7 nM) and high selectivity over alpha 1, D2, and 5-HT2A receptors (Ki > 1000, > 10 000, and > 1000 nM, respectively). Preliminary studies showed that this agent is probably functioning as a partial to full 5-HT1A agonist, and it displayed anxiolytic activity on the social interaction test in mice.
Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense, Madrid, Spain.
M L
ML
López-Rodríguez
M L
ML
Rosado
B
B
Benhamú
M J
MJ
Morcillo
A M
AM
Sanz
L
L
Orensanz
M E
ME
Beneitez
J A
JA
Fuentes
J
J
Manzanares
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D007700:Kinetics; D051379:Mice; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry*; D020891:Raclopride; D051381:Rats; D044402:Receptor, Serotonin, 5-HT2A; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism*; D044263:Receptors, Serotonin, 5-HT1; D012457:Salicylamides / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000138:chemical synthesis / Q000737:chemistry*; D012919:Social Behavior; D013329:Structure-Activity Relationship
D010879:Piperazines; D044402:Receptor, Serotonin, 5-HT2A; D018340:Receptors, Adrenergic, alpha-1; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012457:Salicylamides; D017366:Serotonin Receptor Agonists; D020891:Raclopride; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin