Synthesis of novel imidazobenzodiazepines as probes of the pharmacophore for "diazepam-insensitive" GABAA receptors.
The syntheses of a series of novel imidazobenzodiazepines and their affinities for diazepam sensitive (DS) and diazepam insensitive (DI) GABAA receptors are described. Imidazobenzodiazepines belong to one of the very few chemical families which exhibit high to moderate potency for DI GABAA receptors. Although imidazobenzodiazepines such as Ro 15-4513, 20, are the most potent DI GABAA receptor ligands described to date, their selectivity for DI versus DS GABAA receptors is only marginal. Previous structure-activity relationship (SAR) studies of imidazobenzodiazepines have indicated that the 3- and 8-positions are critical for high-affinity binding to DI GABAA receptors (J. Med. Chem. 1993, 36, 479-490. J. Med. Chem. 1993, 36, 1001-1006. J. Med. Chem. 1993, 36, 1820-1830). In order to determine why the ester function is critical to high affinity at the DI site, we have synthesized several derivatives which have substituents other than an ester at the C(3) position including 3-alkyl-, 3-alkylketo-, 3-alkyl ether, and 3-dialkylamino-substituted imidazobenzodiazepines. The SAR analysis of these compounds when combined with that of several pyrazoloquinolinones indicates that interactions at H1 and L1 as well as interactions at H2 anti to the imidazole N(2) and at a lipophilic pocket (labeled LDi) about the 3-position are required in order for imidazobenzodiazepines to exhibit selectivity and high affinity for DI GABAA receptors. Furthermore, the imidazobenzodiazepines substituted with an electron-donating group (alkoxy function) at position 8 revealed that the change of the substituent at C(8) from an electron-withdrawing to a donating function did not substantially alter either ligand affinity or selectivity for DI GABAA receptors. Thus, a pharmacophore is proposed for DI GABAA receptor ligands, which is characterized by the requirement of a lipophilic pocket LDi about the C(3) position of imidazobenzodiazepines. Using this model, two pyrazoloquinolinone derivatives were designed and synthesized. Their affinities and selectivities for DI GABAA receptors are consistent with those predicted by the DI GABAA receptor pharmacophore. In addition, examination of the in vitro binding data of 3-alkyl ether analogs confirms that the anti conformation of the ester group at the C(3) position of imidazobenzodiazepines (Ro15-4513, 20 series) is preferred at both DI and DS GABAA receptors. This constitutes the first evidence (other than molecular modeling) to support the auxillary involvement of H2 at the DI site and is important with regard to the synthesis of other DI GABAA receptor selective ligands in the future.(ABSTRACT TRUNCATED AT 400 WORDS)
Zhang
P
P
Department of Chemistry, University of Wisconsin-Milwaukee 53201, USA.
Zhang
W
W
Liu
R
R
Harris
B
B
Skolnick
P
P
Cook
J M
JM
D000345:Affinity Labels / Q000378:metabolism; D000818:Animals; D001386:Azides / Q000378:metabolism; D001569:Benzodiazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D003975:Diazepam / Q000494:pharmacology*; D008297:Male; D015335:Molecular Probes; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000737:chemistry* / Q000187:drug effects; D013329:Structure-Activity Relationship
D000345:Affinity Labels; D001386:Azides; D015335:Molecular Probes; D011963:Receptors, GABA-A; D001569:Benzodiazepines; C042957:Ro 15-4513; D003975:Diazepam