Synthesis and 5-HT3 receptor affinity of new quinolinecarboxylic acid derivatives.
A series of quinolinecarboxylic acid amides and an ester with a quinuclidine moiety were synthesized and their in vitro affinities at 5-HT3, 5-HT4, and D2 receptors evaluated by radioligand binding assays. Highest affinity at 5-HT3 receptor corresponded to derivative 5 with Ki = 9.9 nM and with selectivity over 5-HT4 and D2 receptors. Compounds displayed moderate 5-HT3 antagonist activity (ED50 = 10.5-21.5 microg/kg i.v.). The obtained data suggest that the 5-HT3 receptor sites can accommodate the acyl group of the 2-quinoline derivatives. The results indicate the existence of an optimal distance between the lone electron pair of the quinoline nitrogen atom and the azabicyclic nitrogen atom, and a no-pharmacophoric pocket in the 5-HT3 receptor which would hold the fragment at the position 4 of the quinoline ring.
Orjales
A
A
Departamento de Investigación, FAES, Leioa (Vizcaya), Spain.
Alonso-Cires
L
L
López-Tudanca
P L
PL
Tapia
I
I
Labeaga
L
L
Mosquera
R
R
D000818:Animals; D018492:Dopamine Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D006168:Guinea Pigs; D008297:Male; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000378:metabolism; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism*; D044406:Receptors, Serotonin, 5-HT3; D044422:Receptors, Serotonin, 5-HT4; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D018492:Dopamine Antagonists; D011804:Quinolines; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D044422:Receptors, Serotonin, 5-HT4; C059924:quinoline-4-carboxylic acid