(.+-.)-3-Allyl-7-halo-8-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepines as selective high affinity D1 dopamine receptor antagonists: synthesis and structure-activity relationship

Abstract

Substituted 1-phenyl-3-benzazepines form a class of compounds possessing potent and selective affinity for the D1 DA receptor. 7,8-Dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SKF 38393) and its 6-halo analogues are potent and selective D1 receptor agonists. Recently, the 3-allyl derivatives of SKF 38393 and its analogues were described as selective D1 agonists with higher D1 efficacy and CNS potency. In order to extend these results to compounds in the 7-halo-8-hydroxy-substituted antagonist series, we have synthesized and pharmacologically characterized 3-allyl analogues of 7-substituted (Cl, Br, H) 8-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepines. These 3-allyl derivatives were compared with their 3-methyl and 3-unsubstituted analogues in terms of their D1 receptor affinity and selectivity. The results have been used to generate structure-affinity relationships. The D1 receptor affinity, for 3-substitution, is found to be in the order: methyl greater than allyl greater than H. For 7-substitution, the affinity is in the order: Cl = Br greater than H. The 3-allyl compounds show affinity close to that of the parent (3-methyl) compounds while exhibiting a slightly diminished D1 selectivity. However, the greater lipophilicity of the 3-allyl compounds may enable them to cross the blood-brain barrier more readily and thereby exhibit higher in vivo CNS potency. Thus 3-allylbenzazepines have potential as high affinity selective D1 antagonists.

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

“…Thus, treatment of the amide 10 with allyl acetate and a series of palladium catalysts afforded 11 in moderate yields. To improve this transformation, [20] allyl bromide was investigated as a reagent with and without a palladium catalyst present. The reactions mediated by palladium(0) and allyl bromide were faster than their uncatalysed counterparts.…”

Distinct roles of presynaptic dopamine receptors in the differential modulation of the intrinsic synapses of medium-spiny neurons in the nucleus accumbens

“…However, there are potential confounds in such an approach, including instability of DA, differential accessibility of DA and DA antagonists to receptors in the slice and limited reversibility of antagonists due to their lipophilicity. [30-33]. We therefore opted to use D2 and D3 KO mice.…”

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

“…In Scheme 1, the benzazepines 4a-c were synthesized by a modification of the procedure of Baindur et al 36 The 3-substituted-4-methoxyphenylacetonitriles were reduced to the respective (3-substituted-4-methoxyphenyl)ethylamines (la and lb; lc was purchased from Aldrich Chemical Co.) with alane (AIH3) in THF according to the procedure of Yoon et al 37 Compounds la-c were condensed with styrene oxide in THF to obtain the benzyl alcohols 3a-c. Cyclization of 3a-c in a mixture of refluxing trifluoroacetic acid and methanesulfonic acid formed the benzazepines 4a-c in 90-95% yield. A coupling reaction between the benzazepines 4a-c and (IV^V-dimethylamino)butyric acid using dicyclohexylcarbodiimide (DCC) and 1-hydroxybenzotriazole (HOBt)38 gave the amides 5a-c.…”

“…After the THF was removed, the viscous crude product was dissolved in 100 mL of ether, and after 2 h standing white crystalline product was formed which was separated by suction filtration and washed with ether: mp 94 (±)-7-Chloro-8-methoxy-l-phenyl-2,3,4,5-tetrahydro-Lff-3-benzazepine (4a). Cyclization of 3a was performed by modifying the procedure of Baindur et al 36 Product 3a (3.05 g, 10 mmol) was dissolved in 30 mL of trifluoroacetic acid (99%), and then 1.0 mL (10 mmol) of methanesulfonic acid (99%) was added under an atmosphere of argon. The reaction mixture was stirred at reflux for 18 h. After completion of the reaction, the excess of trifluoroacetic acid was evaporated on the rotary evaporator and the remaining viscous mixture was poured into ice-cold H2O (50 mL) and made alkaline with a 15% aqueous NaOH solution.…”

“…O-Demethylation was performed by modifying the procedure of Baindur et al 36 A 0.43 g (1.1 mmol) portion of 6a was dissolved in dry CHClg (10 mL), and then 3.5 mL of BBrg (1 M solution in CHgClg) was added at 0 °C under an atmosphere of argon. The reaction mixture was allowed to stir for 1 h at room temperature, and then 10 mL of methanol (anhydrous) was added dropwise at 0 °C.…”