Specific targeting of peripheral serotonin 5-HT(3) receptors. Synthesis, biological investigation, and structure-activity relationships.
The synthesis and the biological characterization of novel highly selective pyrroloquinoxaline 5-HT(3) receptor (5-HT(3)R) ligands are described. In functional and in vivo biological studies the novel quinoxalines modulated cardiac parameters by direct interaction with myocardial 5-HT(3)Rs. The potent 5-HT(3)R ligands 4h and 4n modulate chronotropy (right atrium) but not inotropy (left atrium) at the cardiac level, being antagonist and partial agonist, respectively. Preliminary pharmacokinetic studies indicate that (S)-4n and 4a, representatives of the novel 5-HT(3)R ligands, possess poor blood-brain barrier permeability, being the prototypes of peripherally acting 5-HT(3)R modulators endowed with a clear-cut pharmacological activity at the cardiac level. The unique properties of 4h and 4n, compared to their previously described centrally active N-methyl analogue 5a, are mainly due to the hydrophilic groups at the distal piperazine nitrogen. These analogues represent novel pharmacological tools for investigating the role of peripheral 5-HT(3)R in the modulation of cardiac parameters.
European Research Centre for Drug Discovery and Development, Siena, Italy.
Elena
E
Morelli
Sandra
S
Gemma
Roberta
R
Budriesi
Giuseppe
G
Campiani
Ettore
E
Novellino
Caterina
C
Fattorusso
Bruno
B
Catalanotti
Salvatore Sanna
SS
Coccone
Sindu
S
Ros
Giuseppe
G
Borrelli
Marco
M
Persico
Isabella
I
Fiorini
Vito
V
Nacci
Pierfranco
P
Ioan
Alberto
A
Chiarini
Michel
M
Hamon
Alfredo
A
Cagnotto
Tiziana
T
Mennini
Claudia
C
Fracasso
Milena
M
Colovic
Silvio
S
Caccia
Stefania
S
Butini
D000818:Animals; D017704:Baroreflex / Q000187:drug effects; D055598:Chemical Phenomena; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D006325:Heart Atria / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008958:Models, Molecular; D009206:Myocardium / Q000378:metabolism*; D011758:Pyrroles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011810:Quinoxalines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011814:Quipazine / Q000031:analogs & derivatives / Q000138:chemical synthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000378:metabolism; D044406:Receptors, Serotonin, 5-HT3 / Q000187:drug effects* / Q000378:metabolism*; D058827:Serotonin 5-HT3 Receptor Agonists; D013329:Structure-Activity Relationship
D011758:Pyrroles; D011810:Quinoxalines; D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3; D058827:Serotonin 5-HT3 Receptor Agonists; D011814:Quipazine