7-Methyl-6,7,8,9,14,15-hexahydro-5H-benz[d]indolo[2,3-g]azecine:  A New Heterocyclic System and a New Lead Compound for Dopamine Receptor Antagonists

Abstract

Partially hydrogenated derivatives of the new heterocyclic ring systems benz[d]indolo[2,3-g]azecine and bisindolo[3,2-d][2, 3-g]azecine were synthesized starting from lactones and amines via the described synthetic methods. In binding assays with rat striatal receptors, 7-methyl-6,7,8,9,14,15-hexahydro-5H-benz[d]indolo[2, 3-g]azecine (LE 300) proved to be of high affinity for the D(1) binding site (K(i) = 0.08 nmol for displacement of [(3)H]SCH23390), being superior in this assay to standards such as butaclamol and SCH23390. This compound was characterized as a dopamine antagonist by conditioned avoidance response test with mice. Thus, LE 300 represents the lead of a new class of dopamine antagonists for future investigations.

Quantitative comparison of functional screening by measuring intracellular Ca2+ with radioligand binding at recombinant human dopamine receptors

“…Compound LE300 was synthesized in the group of Dr Jochen Lehmann (Bonn, Germany), according to Witt et al 14 All other compounds and reagents were obtained at Sigma Chemical unless otherwise stated.…”

Synthesis and 5-HT2A Antagonist Activity of Derivatives of the Novel Heterocycles Indolo[3,2-d]pyrrolo[3,2-g]azecine and Benzo[d]pyrrolo[3,2-g]azecine compared to the Benz[d]indolo[2,3-g]azecine Derivative LE 300

“…Previous radioligand binding experiments have shown that LE 300 (pK i = 7.79 [5] ) is about 6-up to 51-fold less potent than the reference 5-HT 2A -receptor antagonist ketanserin (pK i = 9.41 [17] , 8.46 [18] , 8.93 [19] , 8.80 [20] ). The antagonist potency ratio of 1:17 determined in our functional rat tail artery assay perfectly matches with this range although the absolute affinity tends to be moderately higher (pA 2 = 8.32 versus 9.55, see Table 1).…”

“…These compounds represent hybrid molecules of tryptamine and phenethylamine, linked through the moderately rigid azecine ring system [5] . In radioligand binding studies the most prominent member of this series, compound LE 300 (Chart 1) displays subnanomolar affinity for the rat striatal D 1 receptor and a well-balanced binding profile at D 2 and 5-HT 2A receptors, respectively.…”

Novel Fused Pyrrole Heterocyclic Ring Systems as Structure Analogs of LE 300: Synthesis and Pharmacological Evaluation as Serotonin 5‐HT2A, Dopamine and Histamine H1 Receptor Ligands

“…1) introduced by Lehmann et al [15], revealed a subnanomolar affinity towards the rat striatal D 1 receptor and high functional activity at the 5-HT 2A receptor [15 -17]. The idea behind the synthesis of such a heterocyclic system was to incorporate the substructures of tryptamine and bphenylethylamine moieties into a moderately constrained ten-membered semi-rigid azecine ring [15].…”

“…1) introduced by Lehmann et al [15], revealed a subnanomolar affinity towards the rat striatal D 1 receptor and high functional activity at the 5-HT 2A receptor [15 -17]. The idea behind the synthesis of such a heterocyclic system was to incorporate the substructures of tryptamine and bphenylethylamine moieties into a moderately constrained ten-membered semi-rigid azecine ring [15]. Intensive SAR studies were performed within this novel class of dopamine receptor ligands, including variations in ring size [18], de-indolization of the structure [19], the insertion of an additional oxygen atom into the alicyclus [20,21] and changing one of the aromatic moieties (indole replaced by benzene, thiophene, and 1-methyl-1H-pyrrole, respectively) and its location with respect to each other at the central alicyclic ring [22].…”