Benzimidazole derivatives. 2. Synthesis and structure-activity relationships of new azabicyclic benzimidazole-4-carboxylic acid derivatives with affinity for serotoninergic 5-HT(3) receptors.
A new series of azabicyclic benzimidazole-4-carboxamides 2-21 and -carboxylates 22-30 were synthesized and evaluated for binding affinity at serotoninergic 5-HT(3) and 5-HT(4) receptors in the CNS. Most of the synthesized compounds exhibited high or very high affinity for the 5-HT(3) binding site and low to no significant affinity for the 5-HT(4) receptor. SAR observations indicated that a halogen atom at the 6-position and a nitro group at the 7-position of the benzimidazole ring is the best substitution pattern for 5-HT(3) affinity and 5-HT(3)/5-HT(4) selectivity, as well as no substitution in this ring. (S)-(-)-N-(Quinuclidin-3-yl)benzimidazole-4-carboxamides 2, 8, and 14 bound at central 5-HT(3) sites with high affinity (K(i) = 2.6, 0. 13, and 1.7 nM, respectively) and excellent selectivity over serotonin 5-HT(4) and 5-HT(1A) receptors (K(i) > 1000-10000 nM). Furthermore, these new 5-HT(3) receptor ligands were pharmacologically characterized as potent and selective 5-HT(3) antagonists in the isolated guinea pig ileum (pA(2) = 9.6, 9.9, and 9.1, respectively).
López-Rodríguez
M L
ML
Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense, 28040 Madrid, Spain.
Benhamú
B
B
Morcillo
M J
MJ
Tejada
I D
ID
Orensanz
L
L
Alfaro
M J
MJ
Martín
M I
MI
D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D002462:Cell Membrane / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D004558:Electric Stimulation; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D008297:Male; D015394:Molecular Structure; D009119:Muscle Contraction / Q000187:drug effects; D011812:Quinuclidines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000378:metabolism*; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists / Q000138:chemical synthesis*; D013329:Structure-Activity Relationship
D001562:Benzimidazoles; C402275:N-(1-azabicyclo(2.2.2)oct-3-yl)--6-chlorobenzimidazole-4-carboxamide; C402276:N-(1-azabicyclo(2.2.2)oct-3-yl)-6--chloro-7-nitrobenzimidazole-4-carboxamide; C402274:N-(1-azabicyclo(2.2.2)oct-3-yl)benzimidazole-4-carboxamide; D011812:Quinuclidines; D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists