Synthesis and structure-affinity relationships of 1-[omega-(4-aryl-1-piperazinyl)alkyl]-1-aryl ketones as 5-HT(7) receptor ligands.
Structural requirements for 5-HT(7) receptor affinity and selectivity over that for the 5-HT(1A) receptor were studied on a series of 1-[omega-(4-aryl-1-piperazinyl)alkyl]-1-aryl ketones. The presence of a hydroxy or methoxy substituent on aryl ketone moiety, alkyl chain length, and the nature of N-1-piperazine substituent were explored. 6-[4-(3-Benzisoxazolyl)-1-piperazinyl]-1-(2-hydroxyphenyl)-1-hexanone (40) and its methoxy analogue 43 exhibited high 5-HT(7) receptor affinities (Ki = 2.93 nM and 0.90 nM, respectively) and agonist properties when tested for 5-HT(7) receptor-mediated relaxation of substance P-induced guinea-pig ileum contraction.
Perrone
Roberto
R
Dipartimento Farmaco-Chimico, Università degli Studi di Bari, via Orabona, 4, 70126, Bari, Italy. perrone@farmchim.uniba.it
Berardi
Francesco
F
Colabufo
Nicola A
NA
Lacivita
Enza
E
Leopoldo
Marcello
M
Tortorella
Vincenzo
V
D000818:Animals; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D006224:Cricetinae; D006168:Guinea Pigs; D006801:Humans; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007659:Ketones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D008099:Liver / Q000378:metabolism; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D011985:Receptors, Serotonin / Q000378:metabolism*; D013329:Structure-Activity Relationship
C471875:6-(4-(3-benzisoxazolyl)-1-piperazinyl)-1-(2-hydroxyphenyl)-1-hexanone; C471876:6-(4-(3-benzisoxazolyl)-1-piperazinyl)-1-(2-methoxyphenyl)-1-hexanone; D007555:Isoxazoles; D007659:Ketones; D008024:Ligands; D010879:Piperazines; D011985:Receptors, Serotonin; C104425:serotonin 7 receptor