Novel N-substituted indol-3-ylglyoxylamides probing the LDi and L1/L2 lipophilic regions of the benzodiazepine receptor site in search for subtype-selective ligands.
Novel N-substituted indol-3-ylglyoxylamides (10-37) were synthesized and evaluated as ligands of the benzodiazepine receptor (BzR). In an effort to achieve affinity-based selectivity among BzR subtypes, these compounds were designed to probe the LDi and L2 lipophilic regions. Taking the alpha1-selective benzylindolylglyoxylamides Ia and Ib as leads, we varied the substituent on the benzylamide phenyl ring (compounds 10-23) or replaced the benzyl moiety with alkyl groups (compounds 24-37). The above structural changes gave no shift of selectivity from the alpha1 toward the alpha2 or alpha5 subtypes, thus confirming that a ligand which occupies the LDi region probably exhibits alpha1 selectivity, despite its interactions with other lipophilic areas in the receptor binding cleft. Compound 11 (N-(p-methylbenzyl)-5-nitroindol-3-ylglyoxylamide), which selectively binds with a full agonist efficacy at the alpha1 receptor subtype and displays sedative action, can be regarded as an interesting potential zolpidem-like sedative-hypnotic agent.
Primofiore
Giampaolo
G
Dipartimento di Scienze Farmaceutiche, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy. primofiore@farm.unipi.it
Taliani
Sabrina
S
Da Settimo
Federico
F
Marini
Anna Maria
AM
La Motta
Concettina
C
Simorini
Francesca
F
Patrizi
Maria Paola
MP
Sergianni
Valentina
V
Novellino
Ettore
E
Greco
Giovanni
G
Cosimelli
Barbara
B
Calderone
Vincenzo
V
Montali
Marina
M
Besnard
François
F
Martini
Claudia
C
D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D002417:Cattle; D002460:Cell Line; D002540:Cerebral Cortex / Q000378:metabolism; D058785:GABA-A Receptor Agonists; D006038:Glyoxylates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006993:Hypnotics and Sedatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008968:Molecular Conformation; D009043:Motor Activity / Q000187:drug effects; D011869:Radioligand Assay; D051381:Rats; D013329:Structure-Activity Relationship
D000577:Amides; D058785:GABA-A Receptor Agonists; D006038:Glyoxylates; D006993:Hypnotics and Sedatives; D007211:Indoles; D008024:Ligands; C519518:N-(p-methylbenzyl)-5-nitroindol-3-ylglyoxylamide