1,9-Alkano-bridged 2,3,4,5-tetrahydro-1H-3-benzazepines with affinity for the .alpha.2-adrenoceptor and the 5-HT1A receptor

Abstract

A number of 1,9-alkano-bridged 2,3,4,5-tetrahydro-1H-3-benzazepines were prepared and evaluated for 5-HT1A receptor and alpha 2-adrenoceptor affinity by using radioligand receptor binding techniques. Several compounds displayed 5-HT1A receptor affinity comparable to, or greater than, the known 5-HT1A ligand buspirone. The highest affinity 5-HT1A receptor ligands were N-alkyl-, N-allyl-5-chloro-, and 5-methoxy-1,2,3,4,8,9,10,10a-octahydronaphth[1,8-cd]azapines (4c, 4m, 4n), which had pKi values of 7.9-8.1. The S enantiomer of 4c had a higher affinity for the 5-HT1A receptor than the corresponding R isomer (pKi of 8.2 for (S)-4c vs 7.7 for (R)-4c). These compounds had a relatively low affinity for the alpha 2-adrenoceptor (pKi of 7 or less). On the other hand, the closely related 5-chloro-2-methyl-2,3,4,8,9,9a-hexahydro-1H-indeno[1,7-cd]azepine (3b) had high affinity for both the alpha 2-adrenoceptor (pKi = 8.1) and 5-HT1A receptor (pKi = 7.6). These results indicate that the two receptors may share common recognition sites.

Design, Synthesis and Pharmacological Evaluation of 5-Hydroxytryptamine1aReceptor Ligands to Explore the Three-Dimensional Structure of the Receptor

“…The 5-HT 1A receptor binding studies were performed by a modification of a procedure described previously (Clark et al, 1990). The cerebral cortices of male SpragueDawley rats (Rattus norvegicus albinus) weighing 180 to 200 g were homogenized in 10 volumes of ice-cold Tris buffer (50 mM Tris-HCl, pH 7.7 at 25°C) and centrifuged at 28,000g for 15 min.…”

Domino or Single‐Step Tsuji–Trost/Heck Reactions and Their Application in the Synthesis of 3‐Benzazepines and Azepino[4,5‐b]indole Ring Systems

“…The preparation of both of these classes of compounds could, in theory, come from the same retrosynthetic disconnection. Historically, 3-benzazepines have been prepared through various methods including Friedel-Craftstype approaches, [6] thermal-rearrangement-promoted cyclisations [7] and radical cyclisations, [8] among others. [3,9] Figure 1.…”

Azepino- and Diazepinoindoles: Synthesis and Dopamine Receptor Binding Profiles

“…Treatment of the secondary amine 10 [13] with benzaldehyde and acetic acid resulted in formation of the tricyclic test compound 2.…”

“…To a solution of 10 [13] (80 mg, 0.46 mmol) in MeOH (10 ml) and acetic acid (1 ml) was added benzaldehyde (0.2 ml, 2 mmol). After stirring for 1 h at 60 °C the solution was basified with 2N NaOH and extracted with CH2Cl2 (30 ml).…”

“…The mixture was filtered and the residue washed with MeOH (25 ml). The organic layer was evaporated and the residue was purified by flash chromatography (CH2Cl2/MeOH 9:1) to give 9b (178 mg, 65%) as a colorless solid, 1-Phenyl-1,2,3,4,5,6-hexahydroazepino-1H- [4,5-b]indol-4-on (13) A mixture of 12 (534 mg, 1.5 mmol) and Pd/C (120 mg, 10%) in MeOH (15 ml) was stirred under H2 (1 bar) at room temperature for 16 h. The mixture was filtered through celite and the filtrate was evaporated. …”