ChemInform Abstract: Structural Requirements for Agonist Actions at the Benzodiazepine Receptor: Studies with Analogues of 6‐(Benzyloxy)‐4‐(methoxymethyl)‐β‐carboline‐3‐carboxylic Acid Ethyl Ester.

Abstract

Starting with the title compound (I), the β‐carboline derivatives (II) and (IV) are prepared by known procedures.

Synthesis of novel 2-phenyl-2H-pyrazolo[4,3-c]isoquinolin-3-ols: topological comparisons with analogs of 2-phenyl-2,5-dihydropyrazolo[4,3-c]quinolin-3-(3H)-ones at benzodiazepine receptors

“…In addition, the indolo[3,2-b]isoquinoline 13 has been recently prepared and shown to be inactive (IC50 » 2 µ ) at BzR.10 As reported,3 the diindole 14 exhibits an IC50 of 4 nM, but simple deletion of the N( 7)-H function has completely eliminated the affinity of this diindole to provide the inactive indolo[3,2-6]isoquinoline.10…”

“…This suggests that the keto rather than the proposed enol form is the bioactive form. 4 In the keto form, the quinoline 11 is able to interact at both hydrogen bonding interaction sites A2, Hx of the pharmacophore,3,6 whereas the enol tautomer cannot interact at either site, regardless of the direction of approach of the ligand to the binding site.…”

Dual mode of stimulation by the β‐carboline ZK 91085 of recombinant GABAA receptor currents: molecular determinants affecting its action

“…ZK 91085 was tested for an anticonvulsant action in mice ( Hollinshead et al ., 1990 ). This β‐carboline displayed no effect at 40 mg kg −1 .…”

Ligands of the GABAA Receptor Benzodiazepine Binding Site

“…The interaction of a ligand with both A 2 and H 1 sites of the BZ-binding domain of the receptor (Fig. 5) appears obligatory for inverse agonist activity (39,40). It has also been reported that smaller lipophilic substituents at position 3, which lie close to the plane of the β-carboline ring system, tend to yield inverse agonists, while analogs carrying longer or bulkier substituents at the same position possess antagonist activity (38).…”

“…CNS Drug Reviews, Vol. 5 With respect to substitutions at position 6 of β-carboline (38,39) the benzyl oxygen and benzylamino nitrogen have been closely correlated to the potency of the compound via a recent study which employed a series of 6-benzyloxy and 6-benzylamino analogs to study such effects. Additionally, the phenyl ring of the β-carboline has been shown to play an important role in its hydrophobicity.…”