Synthesis and structure-activity relationships of a new model of arylpiperazines. Part 7: Study of the influence of lipophilic factors at the terminal amide fragment on 5-HT(1A) affinity/selectivity.
The influence of lipophilic factors at the amide fragment of a new series of (+/-)-7a-alkyl-2-[4-(4-arylpiperazin-1-yl)butyl]-1,3-dioxoperhydropyrrolo[1,2-c]imidazoles 2 and of (+/-)-7a-alkyl-2-[(4-arylpiperazin-1-yl)methyl]-1,3-dioxoperhydropyrrolo[1,2-c]imidazoles 3 has been studied. Variations of logP have been carried out by introducing different hydrocarbonated substituents (R(1)) at the position 7a of the bicyclohydantoin, namely the non-pharmacophoric part. All the new compounds exhibit high potency for the 5-HT(1A) receptor; however, affinities for the alpha(1) receptor are high for compounds 2a-l while compounds 3a-f are selective over this adrenergic receptor. On the other hand, differences in logP do not notably affect the K(i) values for the above receptors.
López-Rodríguez
María L
ML
Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense, E-28040 Madrid, Spain. mluzlr@quim.ucm.es
Ayala
David
D
Viso
Alma
A
Benhamú
Bellinda
B
de La Pradilla
Roberto Fernández
RF
Zarza
Fernando
F
Ramos
José A
JA
D000577:Amides / Q000737:chemistry*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D001952:Bridged-Ring Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006827:Hydantoins / Q000737:chemistry*; D050356:Lipid Metabolism; D008055:Lipids / Q000737:chemistry*; D008297:Male; D008958:Models, Molecular; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D044263:Receptors, Serotonin, 5-HT1 / Q000378:metabolism*; D013329:Structure-Activity Relationship
D000577:Amides; D001952:Bridged-Ring Compounds; D006827:Hydantoins; D008055:Lipids; D010879:Piperazines; D018340:Receptors, Adrenergic, alpha-1; D044263:Receptors, Serotonin, 5-HT1