Investigations on the 1-(2-biphenyl)piperazine motif: identification of new potent and selective ligands for the serotonin(7) (5-HT(7)) receptor with agonist or antagonist action in vitro or ex vivo.
Here we report the design, synthesis, and 5-HT(7) receptor affinity of a set of 1-(3-biphenyl)- and 1-(2-biphenyl)piperazines. The effect on 5-HT(7) affinity of various substituents on the second (distal) phenyl ring was analyzed. Several compounds showed 5-HT(7) affinities in the nanomolar range and >100-fold selectivity over 5-HT(1A) and adrenergic α(1) receptors. 1-[2-(4-Methoxyphenyl)phenyl]piperazine (9a) showed 5-HT(7) agonist properties in a guinea pig ileum assay but blocked 5-HT-mediated cAMP accumulation in 5-HT(7)-expressing HeLa cells.
Dipartimento Farmaco-Chimico, Università degli Studi di Bari A. Moro, via Orabona, 4, 70125, Bari, Italy.
Enza
E
Lacivita
Daniela
D
Patarnello
Nikolas
N
Stroth
Antonia
A
Caroli
Mauro
M
Niso
Marialessandra
M
Contino
Paola
P
De Giorgio
Pantaleo
P
Di Pilato
Nicola A
NA
Colabufo
Francesco
F
Berardi
Roberto
R
Perrone
Per
P
Svenningsson
Peter B
PB
Hedlund
Marcello
M
Leopoldo
D000818:Animals; D006168:Guinea Pigs; D006367:HeLa Cells; D006801:Humans; D007082:Ileum / Q000187:drug effects / Q000378:metabolism; D008024:Ligands; D008958:Models, Molecular; D008970:Molecular Weight; D000077489:Piperazine; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D011487:Protein Conformation; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D011985:Receptors, Serotonin / Q000737:chemistry / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D008024:Ligands; D010879:Piperazines; D018340:Receptors, Adrenergic, alpha-1; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C104425:serotonin 7 receptor; D000077489:Piperazine