Novel, potent, and selective quinoxaline-based 5-HT(3) receptor ligands. 1. Further structure-activity relationships and pharmacological characterization.
We investigated the pharmacological profile of a novel series of quinoxaline-based 5-HT(3) receptor ligands bearing an extra basic moiety on the piperazine N-4. High affinity and selectivity were dependent on the electronic properties of the substituents, and at cardiac level 3a and 3c modulated chronotropy but not inotropy. In von Bezold-Jarisch reflex test 3a-c were partial agonists while 3i was a full agonist. Preliminary pharmacokinetic studies indicated that 3a is a brain penetrating agent.
Butini
Stefania
S
European Research Centre for Drug Discovery and Development, 53100 Siena, Italy.
Budriesi
Roberta
R
Hamon
Michel
M
Morelli
Elena
E
Gemma
Sandra
S
Brindisi
Margherita
M
Borrelli
Giuseppe
G
Novellino
Ettore
E
Fiorini
Isabella
I
Ioan
Pierfranco
P
Chiarini
Alberto
A
Cagnotto
Alfredo
A
Mennini
Tiziana
T
Fracasso
Claudia
C
Caccia
Silvio
S
Campiani
Giuseppe
G
D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D054333:Drug Partial Agonism; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D008024:Ligands; D009200:Myocardial Contraction / Q000187:drug effects; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011810:Quinoxalines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D012018:Reflex / Q000187:drug effects; D058827:Serotonin 5-HT3 Receptor Agonists; D058831:Serotonin 5-HT3 Receptor Antagonists; D013329:Structure-Activity Relationship
D008024:Ligands; D011758:Pyrroles; D011810:Quinoxalines; D058827:Serotonin 5-HT3 Receptor Agonists; D058831:Serotonin 5-HT3 Receptor Antagonists