(.+-.)-(Aminoalkyl)benzazepine Analogs: Novel Dopamine D1 Receptor Antagonists

Abstract

(+/-)-(N-Alkylamino)benzazepine analogs were prepared as novel dopamine D1 receptor antagonists to further elucidate the role of these receptor subtypes in the pharmacology and toxicology of cocaine. In the first series of compounds, (+/-)-7-chloro-8-hydroxy-3- [6-(N,N-dimethylamino)-hexyl]-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepi ne (15) showed the highest affinity (Ki = 49.3 nM) and subtype-selectivity for dopamine D1 over dopamine D2, 5-HT2a, and 5-HT2c receptors. Compounds 7a [(+/-)-7-Chloro-8-hydroxy-3-[4-(N,N-dimethylamino)butyl]-1-phenyl- 2,3,4,5-tetrahydro-1H-3-benzazepine], 11 [(+/-)-7-chloro-8-hydroxy-3-[6-[(N,N-dimethylamino)hexyl]-1- phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-cyanoborane], and 15 were moderately potent dopamine D1 receptor antagonists as evidenced by their ability to block dopamine-stimulated adenylyl cyclase activity in rat caudate (predicted Ki values = 60, 34, and 21 nM, respectively). Compound 7a appears to be unique in that, despite its relatively potent inhibition of dopamine stimulated adenylyl cyclase, it demonstrated relatively weak binding affinity at the dopamine D1 receptors (Ki = 811 nM). Unlike previously reported N-alkylbenzazepines, where a significant loss in dopamine D1 receptor binding affinity was observed when successive increases in the alkyl side chain size at the benzazepine nitrogen were made, several of these novel N-alkylamino analogs demonstrated high-affinity binding with an optimal chain length of six carbons. This initial series of compounds appears to be identifying another binding domain on the dopamine D1 receptor protein that has not previously been characterized and that accepts an amino function. Further, these compounds may serve as templates for the design of peripherally active dopamine D1 receptor antagonists.

Quantitative Structure−Activity Relationship Modeling of Dopamine D1Antagonists Using Comparative Molecular Field Analysis, Genetic Algorithms−Partial Least-Squares, and K Nearest Neighbor Methods

“…The CoMFA fields generated from these studies predict improved affinity for compounds possessing positively charged substituents extending from the tertiary nitrogen common to dopaminergic antagonists. This prediction is in accord with previously reported data regarding the extended chain N -substituted compounds 13 − 16 , , although these drugs possess lower affinity in our biological assays. The prediction that negatively charged substituents in the position analogous to the 7-position of SCH23390 would improve affinity is probably based on the rank order of affinity of various halogen-substituted compounds, with more negatively charged chlorine-substituted compounds more potent than iodinated or unsubstituted compounds.…”

Isothiocyanate Derivatives of 9-[3-(cis-3,5-Dimethyl-1-piperazinyl)propyl]- carbazole (Rimcazole): Irreversible Ligands for the Dopamine Transporter

“…As the chain length increases further (to three and then six carbons) the affinity begins to increase, presumably due to interactions at another binding domain. The initial decrease, followed by an increase in affinity on lengthening of the tether between the functional group and the pharmacophore, has previously been observed in other series of receptor ligands …”

“…Method B: CBz Deprotection. The CBz-protected amine was dissolved in CH 3 CN (5 mL/mmol) and the iodotrimethylsilane then added (3.6 equiv). The solution was stirred at room temperature for 1 h before quenching with MeOH (0.5× CH 3 CN vol).…”

An Efficient Approach for the Construction of Benzazepine and Benzoxepine Derivatives

“…Among these compounds, benzazepine and benzoxepine derivatives are of great importance. Some commercial drugs such as galantamine contain the benzazepine framework,7 and a recent research indicates that many compounds containing this moiety appear to be novel and prominent dopamine D1/D5 receptor antagonists 8. Meanwhile, several benzoxepines are found to possess antibiotic activities9 and potentially considered as bronchodilators and antihypertensives 9d.…”