Downstream Allosteric Modulation of NMDA Receptors by 3-Benzazepine Derivatives.

N-Methyl-D-aspartate receptors (NMDARs) composed of different splice variants display distinct pH sensitivities and are crucial for learning and memory, as well as for inflammatory or injury processes. Dysregulation of the NMDAR has been linked to diseases like Parkinson's, Alzheimer's, schizophrenia, and drug addiction. The development of selective receptor modulators, therefore, constitutes a promising approach for numerous therapeutical applications. Here, we identified (R)-OF-NB1 as a promising splice variant selective NMDAR antagonist. We investigated the interaction of (R)-OF-NB1 and NMDAR from a biochemical, bioinformatical, and electrophysiological perspective to characterize the downstream allosteric modulation of NMDAR by 3-benzazepine derivatives. The allosteric modulatory pathway starts at the ifenprodil binding pocket in the amino terminal domain and immobilizes the connecting α5-helix to the ligand binding domain, resulting in inhibition. In contrast, the exon 5 splice variant GluN1-1b elevates the NMDARs flexibility and promotes the open state of its ligand binding domain.

Structure-Activity Relationship Studies on 6-Chloro-1-phenylbenzazepines Leads to the Identification of a New Dopamine D1 Receptor Antagonist.

The 1-phenylbenzazepine template has yielded a number of D1R-like ligands, which, though useful as pharmacological tools, have significant drawbacks in terms of selectivity versus D5R as well as pharmacokinetic behavior. A number of 1-phenylbenzazepines contain a 6-chloro functional group, but extensive SAR studies around the 6-chloro-1-phenylbenzazepine framework have not been reported in the literature. To further understand the tolerance of the 6-chloro-1-phenylbenzazepine template for various substituent groups towards affinity and selectivity at D1R, we synthesized two series of analogs with structural variations at the C-7, C-8, N-3, C-3' and C-4' positions. The series 2 analogs differed from series 1 analogs in possessing a nitrogenated functionality at C-8 and lacked a C-4' substituent, but were otherwise similar. Analogs were assessed for affinity at D1R, D2R and D5R. For both series, we found that the analogs lacked affinity for D2R and showed modest D1R versus D5R selectivity. For series 1 analogs, an N-3 methyl substituent group was better tolerated than N-H or an N-3 allyl substituent. The C-8 position appears to be tolerant of amino and methanesulfonamide substituents for high D1R affinity, but C-8 amides displayed low to moderate D1R affinities. A C-3' methyl substituent appeared to be critical for the D1R affinity of some analogs, but the C-4' substituents tried (hydroxy and methoxy; series 1) did not result in any significant boost in D1R affinity. Compound 15a was the most potent and selective D1R ligand identified from these studies (Ki at D1R = 30 nM; 6-fold selectivity versus D5R). Further functional activity assessments indicate that 15a functions as a D1R antagonist towards cAMP-mediated signaling. The predicted drug-like properties of 15a are encouraging for further pharmacological assessments on the compound.

Genome Mining Discovery of a New Benzazepine Alkaloid Pseudofisnin A from the Marine Fungus Neosartorya pseudofischeri F27-1.

l-Kynurenine (Kyn) is an intermediate in the kynurenine pathway and is also found to be a building block or biosynthetic precursor to bioactive natural products. Recent studies revealed that l-Kyn can be incorporated via nonribosomal peptide synthetase (NRPS) biosynthetic routes to generate 1-benzazepine-containing compounds, while 1-benzazepine is a pharmaceutically important scaffold that is rarely found in natural products. Using a core biosynthetic enzyme-guided genome-mining approach, we discovered a biosynthetic gene cluster from Neosartorya pseudofischeri and identified that it encodes for the biosynthesis of pseudofisnins, novel 1-benzazepine-containing compounds. The biosynthetic pathway of pseudofisnins was elucidated through in vivo and in vitro experiments. The methyltransferase PseC from the pathway was biochemically characterized to be an iterative methyltransferase that catalyzes off-NRPS line di-methylation on an amine group.

SPION nanoparticles for delivery of dopaminergic isoquinoline and benzazepine derivatives.

Superparamagnetic iron nanoparticles (SPIONs) have become one of the most useful colloidal systems in nanomedicine. We report here the preparation of new hybrid core@shell systems based on SPION nanoparticles coated with a SiO2 shell (SPION@SiO2) and functionalized with carboxyl groups (SPION@SiO2-COOH). A series of new N-alkylamino- and N-alkylamido-terminated 1-phenyl- tetrahydroisoquinolines (THIQs) and 3-tetrahydrobenzazepines (THBs) derivatives presenting -SMe and -Cl groups, respectively, with potential dopaminergic activity, are synthesized and incorporated to the hybrid system. We include the synthetic details for THIQs and THBs derivatives preparation and investigate the influence of the terminal-functional group as well as the number of carbon atoms linked to THIQ and THB molecules during the coupling to the SPION@SiO2-COOH. Nuclear magnetic resonance (NMR) and electron ionization mass spectrometry (EI-MS) are used to characterize the synthesized THIQs and THBs. High-angle annular dark-field transmission electron microscopy (HAADF-TEM), energy dispersive X-ray transmission electron microscopy (EDX-TEM), and proton high-resolution magic angle spinning NMR spectroscopy1H HRMAS-NMR) are used to confirm the presence of THB and THIQ molecules onto the surface of the nanoparticles. The hybrid SPION@SiO2-THIQ and THB systems show significant activity toward the D2 receptor, reaching Ki values of about 20 nM, thus having potential application in the treatment of central nervous system (CNS) diseases.

Further studies on C2'-substituted 1-phenylbenzazepines as dopamine D1 receptor ligands.

The 1-phenylbenzazepine scaffold has yielded several D1R targeting ligands, but some gaps remain in our understanding of the structure-activity relationships in this scaffold. In particular, there is a paucity of studies that have investigated the effects of substituents at the C2' position of 1-phenylbenzazepines on their affinity and selectivity towards D1R. In this study, a set of methyl- and fluoro- C2'-substituted 1-phenylbenzazepines, with ring A catechol or 8-hydroxy-7-methoxy moieties in tandem with N-methyl or N-allyl substituent groups, was synthesized and evaluated for affinity at a subset of dopamine receptors - D1R, D2R and D5R. These studies indicate that an N-methyl group is generally preferred over N-unsubstituted or N-allyl groups for strong D1R affinity. In addition, it was revealed that compounds with a ring A 8-hydroxy-7-methoxy motif displayed stronger D1R affinity than analogous compounds with a ring A catechol moiety. Furthermore, the presence of a C2' substituent does not significantly impact D1R selectivity over D5R. However, for all analogs assessed, D1R selectivity over D2R was maintained. D1R vs D5R selectivity was generally poor or modest (less than 10-fold) among members of the series. A new high affinity selective D1R ligand - 10b (Ki = 5.7 nM), was identified in this study; further pharmacological characterization indicates that 10b is an antagonist at D1R (IC50 = 10.7 nM). Docking studies on 10b indicate that a number of interactions with hydrophobic residues (Trp321, Val317, Phe313, Phe289, Phe288, Phe285, Phe203, Tyr194, Leu190, Ser188, His 164, Ile104, Val100 and Trp99) in addition to the typical N-Asp103 salt bridge are important for its D1R affinity.

Recent Advances in the Development of Catalytic Methods that Construct Medium-ring Lactams, Partially Saturated Benzazepines and their Derivatives.

Recent catalytic methods to construct medium-sized lactams and partially saturated benzazepines and their derivatives are surveyed. The review is divided into the following sections: 1 Introduction 2 Non-Transition Metal Catalyzed Reactions 2.1 Beckmann Rearrangement 2.2 Non-Beckmann Rearrangement Reactions 2.3 Multi-component reactions 3 Transition Metal-Catalyzed Reactions 3.1 Au-catalyzed reactions to access medium-sized N-heterocycles 3.2 Reactions involving a metal η3-complex catalytic intermediate 3.3 Transition metal-catalyzed reactions of strained cycloalkanes 4 Conclusions.

Design, synthesis and biological evaluation of brain penetrant benzazepine-based histone deacetylase 6 inhibitors for alleviating stroke-induced brain infarction.

Histone deacetylase 6 (HDAC6) has become a promising therapeutic target for central nervous system diseases due to its more complex protein structure and biological functions. However, low brain penetration of reported HDAC6 inhibitors limits its clinical application in neurological disorders. Therefore, the benzazepine, a brain-penetrant rigid fragment, was utilized to design a series of selective HDAC6 inhibitors to improve brain bioavailability. Various synthetic strategies were applied to assemble the tetrahydro-benzazepine ring, and 22 compounds were synthesized. Among them, compound 5 showed low nanomolar potency and strong isozyme selectivity for the inhibition of HDAC6 (IC50 = 1.8 nM, 141-fold selectivity over HDAC1) with efficient binding patterns like coordination with the zinc ion and π-π stacking effect. Western blot results showed it could efficiently transport into SH-SY5Y cells and selectively enhance the acetylation level of α-tubulin with a moderate effect on Histone H3. Notably, pharmacokinetic studies demonstrated that compound 5 (brain/plasma ratio of 2.30) had an excellent ability to penetrate the blood-brain barrier of C57 mice. In male rats with transient middle cerebral artery occlusion (MCAO), compound 5 significantly reduced the cerebral infarction from 21.22% to 11.47% and alleviated neurobehavioral deficits in post-ischemic treatment, which provided a strong rationale for pursuing HDAC6-based therapies for ischemic stroke.

Design, synthesis, biological evaluation and docking study of novel quinazoline derivatives as EGFR-TK inhibitors.

Background: Quinazoline-based compounds have been proved effective in the treatment of cancers for years. Materials & methods: The structural features of several inhibitors of EGFR were integrated and quinazolines with a benzazepine moiety at the 4-position were constructed. Results: Most of the compounds exhibited excellent antitumor activities. Compound 33e showed excellent antitumor activities against the four tested cell lines (IC50: 1.06-3.55 µM). The enzymatic, signaling pathways and apoptosis assay of 33e were subsequently carried out to study the action of the mechanism. Conclusion: Compound 33e with a benzazepine moiety at the 4-position can be screened in this study and provides useful information for the design of EGFR-T790M inhibitors, which deserve additional research.

Production of benzazepine derivatives via four-component reaction of isatins: study of antioxidant activity.

In current research, benzazepine derivative is synthesized via a new process of four-component reaction of isatin or its derivatives, α-haloketones, activated acetylenic compounds, isoquinoline and potassium fluoride/clinoptilolite nanoparticles (KF/CP NPs) in acidic solution of H2O2 in water at room temperature. Also, antioxidation property of some prepared benzazepines is investigated by employing trapping diphenyl-picrylhydrazine (DPPH) radical and ability of ferric reduction experiment. Among investigated compounds, compounds 5c have good results relative to BHT and TBHQ as standard antioxidant. Also, the Gram-positive and Gram-negative bacteria disk diffusion research is used for the confirmation of antimicrobial power of some prepared benzazepines. The achieved outcomes of disk diffusion experiment showed that these compounds avoided the growth of bacteria. Our procedure has a few benefits relative to reported method such as good rate of reaction, product with high efficiency, simple removal of catalyst from mixture of reaction. In the yield of the product, KF/clinoptilolite nanoparticles show a satisfactory recyclable activity.

Synthesis and dopamine receptor pharmacological evaluations on ring C ortho halogenated 1-phenylbenzazepines.

A series of 1-phenylbenzazepines containing bromine or chlorine substituents at the ortho position of the appended phenyl ring (2'-monosubstituted or 2',6'- disubstituted patterns) were synthesized and evaluated for affinity towards dopamine D1R, D2R and D5R. As is typical of the 1-phenylbenzazepine scaffold, the compounds displayed selectivity towards D1R and D5R; analogs generally lacked affinity for D2R. Interestingly, 2',6'-dichloro substituted analogs showed modest D5R versus D1R selectivity whereas this selectivity was reversed in compounds with a 2'-halo substitution pattern. Compound 10a was identified as a D1R antagonist (Ki = 14 nM; IC50 = 9.4 nM).

Synthesis, pharmacological evaluations, and molecular docking studies on a new 1,3,4,11b-tetrahydro-1H-fluoreno[9,1-cd]azepine framework: Rigidification of D1 receptor selective 1-phenylbenzazepines and discovery of a new 5-HT6 receptor scaffold.

The novel 1,3,4,11b-tetrahydro-1H-fluoreno[9,1-cd]azepine framework, a structurally rigidified variant of the 1-phenylbenzazepine template, was synthesized via direct arylation as a key reaction. Evaluation of the binding affinities of the rigidified compounds across a battery of serotonin, dopamine, and adrenergic receptors indicates that this scaffold unexpectedly has minimal affinity for D1 and other dopamine receptors and is selective for the 5-HT6 receptor. The affinity of these systems at the 5-HT6 receptor is significantly influenced by electronic and hydrophobic interactions as well as the enhanced rigidity of the ligands. Molecular docking studies indicate that the reduced D1 receptor affinity of the rigidified compounds may be due in part to weaker H-bonding interactions between the oxygenated moieties on the compounds and specific receptor residues. Key receptor-ligand H-bonding interactions, salt bridges, and π-π interactions appear to be responsible for the 5-HT6 receptor affinity of the compounds. Compounds 10 (6,7-dimethoxy-2,3,4,11b-tetrahydro-1H-fluoreno[9,1-cd]azepine) and 12 (6,7-dimethoxy-2-methyl-2,3,4,11b-tetrahydro-1H-fluoreno[9,1-cd]azepine) have been identified as structurally novel, high affinity (Ki  = 5 nM), selective 5-HT6 receptor ligands.

Enantioseparation of ß-carboline, tetrahydroisoquinoline and benzazepine analogues of pharmaceutical importance: Utilization of chiral stationary phases based on polysaccharides and sulfonic acid modified Cinchonaalkaloids in high-performance liquid and subcritical fluid chromatography.

High-performance liquid chromatographic (HPLC) and subcritical fluid chromatographic (SFC) separations of the enantiomers of structurally diverse, basic ß-carboline, tetrahydroisoquinoline and benzazepine analogues of pharmacological interest were performed applying chiral stationary phases (CSPs) based on (i) neutral polysaccharides- and (ii) zwitterionic sulfonic acid derivatives of Cinchona alkaloids. The aim of this work was to reveal the influence of structural peculiarities on the enantiorecognition on both types of CSP through the investigation of the effects of the composition of the bulk solvent, the structures of the chiral analytes (SAs) and chiral selectors (SOs) on retention and stereoselectivity. As a general tendency, valid for all polysaccharide SOs studied, the increase of the concentration of the apolar component in the mobile phase (n-hexane for LC or liquid CO2 for SFC) was found to significantly increase retention, which in most cases, was accompanied with increased selectivity and resolution. In a way, similar behaviour was registered for the zwitterionic SOs. In polar ionic mode employing eluent systems composed of methanol and acetonitrile with organic acid and base additives, moderate increases in retention factor, selectivity and resolution were observed with increasing acetonitrile content. However, under SFC conditions, an extremely high increase in retention was observed with increased CO2 content, while selectivity and resolution changed only slightly. Thermodynamic parameters derived from temperature dependence studies revealed that separations are controlled by enthalpy.

High-performance liquid chromatographic and subcritical fluid chromatographic separation of α-arylated ß-carboline, N-alkylated tetrahydroisoquinolines and their bioisosteres on polysaccharide-based chiral stationary phases.

New, pharmacologically interesting chiral amino compounds, namely, stereoisomers of α-hydroxynaphthyl-ß-carboline, benz[d]azepine and benz[c]azepine analogs as well as N-α-hydroxynaphthylbenzyl-substituted isoquinolines were enantioseparated by high-performance liquid chromatographic and subcritical fluid chromatographic methods on polysaccharide-based chiral stationary phases. Separation of the stereoisomers was optimized in both subcritical fluid chromatography and normal phase liquid chromatographic modes by investigating the effects of the composition of the bulk solvent, temperature, and the structures of the analytes and selectors. Both normal phase liquid chromatography and subcritical fluid chromatography exhibited satisfactory performance, albeit with somewhat different effectiveness in the separation of the stereoisomers studied. The optimized methods offer the possibility to apply preparative-scale separations thereby enabling further pharmacological investigations of the enantiomers.

Unusual thermolysis of aza-cyclic allene under microwave conditions: crystal structure of (3RS,3aSR,8RS,8aRS)-methyl 5,6-dimeth-oxy-3a,10-dimethyl-1-phenyl-3,3a,8,8a-tetra-hydro-3,8-(epimino-methano)-cyclo-penta-[a]indene-2-carboxyl-ate from synchrotron X-ray diffraction.

The title compound, C25H27NO4 (I), the product of the unusual thermolysis of aza-cyclic allene methyl 10,11-dimeth-oxy-3,8-dimethyl-6-phenyl-3-aza-benzo[d]cyclo-deca-4,6,7-triene-5-carboxyl-ate, represents a bicyclic heterosystem and crystallizes in the monoclinic space group P21/c with three crystallographically independent mol-ecules in the unit cell. These independent mol-ecules adopt very similar geometries and differ only in the conformations of the two meth-oxy substituents on the benzene ring. In two of the three independent mol-ecules, both meth-oxy groups are almost coplanar with the benzene ring [the C-C-O-Me torsion angles are 10.8 (2), 12.3 (2), 9.1 (2) and 13.6 (3)°], whereas in the third mol-ecule, one of the meth-oxy groups is practically coplanar to and the other meth-oxy group is roughly perpendicular to the benzene ring, the C-C-O-Me torsion angles being 14.1 (2) and 76.5 (2)°. The mol-ecule of (I) comprises a fused tetra-cyclic system containing two five-membered rings (cyclo-pentenes) and two six-membered rings (piperidine and benzene). The five-membered rings have the usual envelope conformation, with the methyl-subsituted C atom as the flap in each molecule, and the six-membered piperidine ring has a chair conformation. The methyl substituent at the N atom occupies the sterically favourable equatorial position. The carboxyl-ate group lies almost within the basal plane of the parent cyclo-pentene ring [making dihedral angle of 11.68 (8), 18.94 (9) and 15.16 (9)° in the three independent mol-ecules], while the phenyl substituent is twisted by 48.26 (6), 42.04 (6) and 41.28 (6)° (for the three independent mol-ecules) relative to this plane. In the crystal, mol-ecules of (I) form stacks along the b-axis direction. The mol-ecules are arranged at van der Waals distances.

Synthesis and Biological Evaluation of Novel Multi-target-Directed Benzazepines Against Excitotoxicity.

Excitotoxicty, a key pathogenic event is characteristic of the onset and development of neurodegeneration. The glutamatergic neurotransmission mediated through different glutamate receptor subtypes plays a pivotal role in the onset of excitotoxicity. The role of NMDA receptor (NMDAR), a glutamate receptor subtype, has been well established in the excitotoxicity pathogenesis. NMDAR overactivation triggers excessive calcium influx resulting in excitotoxic neuronal cell death. In the present study, a series of benzazepine derivatives, with the core structure of 3-methyltetrahydro-3H-benzazepin-2-one, were synthesised in our laboratory and their NMDAR antagonist activity was determined against NMDA-induced excitotoxicity using SH-SY5Y cells. In order to assess the multi-target-directed potential of the synthesised compounds, Aß1-42 aggregation inhibitory activity of the most potent benzazepines was evaluated using thioflavin T (ThT) and Congo red (CR) binding assays as Aß also imparts toxicity, at least in part, through NMDAR overactivation. Furthermore, neuroprotective, free radical scavenging, anti-oxidant and anti-apoptotic activities of the two potential test compounds (7 and 14) were evaluated using primary rat hippocampal neuronal culture against Aß1-42-induced toxicity. Finally, in vivo neuroprotective potential of 7 and 14 was assessed using intracerebroventricular (ICV) rat model of Aß1-42-induced toxicity. All of the synthesised benzazepines have shown significant neuroprotection against NMDA-induced excitotoxicity. The most potent compound (14) showed relatively higher affinity for the glycine binding site as compared with the glutamate binding site of NMDAR in the molecular docking studies. 7 and 14 have been shown experimentally to abrogate Aß1-42 aggregation efficiently. Additionally, 7 and 14 showed significant neuroprotective, free radical scavenging, anti-oxidant and anti-apoptotic properties in different in vitro and in vivo experimental models. Finally, 7 and 14 attenuated Aß1-42-induced tau phosphorylation by abrogating activation of tau kinases, i.e. MAPK and GSK-3ß. Thus, the results revealed multi-target-directed potential of some of the synthesised novel benzazepines against excitotoxicity.

Crystal structures of five new substituted tetrahydro-1-benzazepines with potential antiparasitic activity.

Tetrahydro-1-benzazepines have been described as potential antiparasitic drugs for the treatment of chagas disease and leishmaniasis, two of the most important so-called `forgotten tropical diseases' affecting South and Central America, caused by Trypanosoma cruzi and Leishmania chagasi parasites, respectively. Continuing our extensive work describing the structural characteristics of some related compounds with interesting biological properties, the crystallographic features of three epoxy-1-benzazepines, namely (2SR,4RS)-6,8-dimethyl-2-(naphthalen-1-yl)-2,3,4,5-tetrahydro-1H-1,4-epoxy-1-benzazepine, (1), (2SR,4RS)-6,9-dimethyl-2-(naphthalen-1-yl)-2,3,4,5-tetrahydro-1H-1,4-epoxy-1-benzazepine, (2), and (2SR,4RS)-8,9-dimethyl-2-(naphthalen-1-yl)-2,3,4,5-tetrahydro-1H-1,4-epoxy-1-benzazepine, (3), all C22H21NO, and two 1-benzazepin-4-ols, namely 7-fluoro-cis-2-[(E)-styryl]-2,3,4,5-tetrahydro-1H-1-benzazepin-4-ol, C18H18FNO, (4), and 7-fluoro-cis-2-[(E)-pent-1-enyl]-2,3,4,5-tetrahydro-1H-1-benzazepin-4-ol, C15H20FNO, (5), are described. Some peculiarities in the crystallization behaviour were found, involving significant variations in the crystalline structures as a result of modest changes in the peripheral substituents in (1)-(3) and the occurrence of discrete disorder due to the molecular overlay of enantiomers with more than one conformation in (5). In particular, an interesting phase change on cooling was observed for compound (5), accompanied by an approximate fourfold increase of the unit-cell volume and a change of the Z' value from 1 to 4. This transition is a consequence of the partial ordering of the pentenyl chains in half of the molecules breaking half of the -3 symmetry axes observed in the room-temperature structure of (5). The structural assembly in all the title compounds is characterized by not only (N,O)-H...(O,N) hydrogen bonds, but also by unconventional C-H...O contacts, resulting in a wide diversity of packing.

Regioselective alkylation of 1,3,4,5-tetrahydrobenzo[d]azepin-2-one and biological evaluation of the resulting alkylated products as potentially selective 5-HT2c agonists.

The benzazepine ring system has offered interesting CNS-active medicinal agents. Taking this privileged structure as the basic scaffold, [Formula: see text] and/or [Formula: see text]-alkylated benzazepin-2-one derivatives and their reduced analogs have been prepared as potential [Formula: see text] receptor agonists. The selective alkylation at the [Formula: see text] and/or [Formula: see text] positions of this seven-membered lactam ring is here reported for the first time under different reaction conditions. The synthesized compounds were evaluated for their biological profile as potential [Formula: see text] agonists using a classic pharmacological approach. Three derivatives (15, 17, and 20) have shown promising [Formula: see text] agonistic activity which can be further optimized as anti-obesity agents for the treatment of male sexual dysfunction. Further, a homology model for [Formula: see text] receptor was generated using MODELLER, and ligand-receptor interactions for these potential molecules were studied.

Identification of G protein-biased agonists that fail to recruit ß-arrestin or promote internalization of the D1 dopamine receptor.

The D1 dopamine receptor (D1R) has been implicated in numerous neuropsychiatric disorders, and D1R-selective ligands have potential as therapeutic agents. Previous studies have identified substituted benzazepines as D1R-selective agonists, but the in vivo effects of these compounds have not correlated well with their in vitro pharmacological activities. A series of substituted benzazepines, and structurally dissimilar D1R-selective agonists, were tested for their functional effects on D1R-mediated cAMP accumulation, D1R-promoted ß-arrestin recruitment, and D1R internalization using live cell functional assays. All compounds tested elicited an increase in the level of cAMP accumulation, albeit with a range of efficacies. However, when the compounds were evaluated for ß-arrestin recruitment, a subset of substituted benzazepines, SKF83959, SKF38393, SKF82957, SKF77434, and SKF75670, failed to activate this pathway, whereas the others showed similar activation efficacies as seen with cAMP accumulation. When tested as antagonists, the five biased compounds all inhibited dopamine-stimulated ß-arrestin recruitment. Further, D1R internalization assays revealed a corroborating pattern of activity in that the G protein-biased compounds failed to promote D1R internalization. Interestingly, the biased signaling was unique for the D1R, as the same compounds were agonists of the related D5 dopamine receptor (D5R), but revealed no signaling bias. We have identified a group of substituted benzazepine ligands that are agonists at D1R-mediated G protein signaling, but antagonists of D1R recruitment of ß-arrestin, and also devoid of agonist-induced receptor endocytosis. These data may be useful for interpreting the contrasting effects of these compounds in vitro versus in vivo, and also for the understanding of pathway-selective signaling of the D1R.

Novel 2,4-Diarylaminopyrimidine Analogues (DAAPalogues) Showing Potent c-Met/ALK Multikinase Inhibitory Activities.

By repurposing a typical dopamine D1/D5 receptor agonist motif, C1-substituted-N3-benzazepine or benzazecine, into the classical RTK inhibitor 2,4-diaminopyrimidine skeleton, a series of new 2,4-diarylaminopyrimidine analogues (DAAPalogues) were developed. Compounds 7 and 8a were identified possessing high potency against both c-Met and ALK kinases. Compound 8a displayed appreciable antitumor efficacy at the dose of 1 mg/kg in the ALK-driven BF3/EML4-ALK xenograft mice model.

Four related benzazepine derivatives in a reaction pathway leading to a benzazepine carboxylic acid: hydrogen-bonded assembly in zero, one, two and three dimensions.

(2R*,4S*)-Methyl 2,3,4,5-tetrahydro-1,4-epoxy-1H-benz[b]azepine-2-carboxylate, C12H13NO3, (I), and its reduction product (2R*,4S*)-methyl 4-hydroxy-2,3,4,5-tetrahydro-1H-benz[b]azepine-2-carboxylate, C12H15NO3, (II), both crystallize as single enantiomers in the space group P212121, while the hydrolysis product (2RS,4SR)-4-hydroxy-2,3,4,5-tetrahydro-1H-benz[b]azepine-2-carboxylic acid, C11H13NO3, (III), and the lactone (2RS,5SR)-8-(trifluoromethoxy)-5,6-dihydro-1H-2,5-methanobenz[e][1,4]oxazocin-3(2H)-one, C12H10F3NO3, (IV), both crystallize as racemic mixtures in the space group P21/c. The molecules of compound (IV) are linked into centrosymmetric R2(2)(10) dimers by N-H···O hydrogen bonds, and those of compound (I) are linked into chains by C-H···π(arene) hydrogen bonds. A combination of O-H···O and O-H···N hydrogen bonds links the molecules of compound (III) into sheets containing equal numbers of R4(4)(14) and R4(4)(26) rings, and a combination of C-H···π(arene) hydrogen bonds and three-centre O-H···(N,O) hydrogen bonds links the molecules of compound (II) into a three-dimensional framework structure. Comparisons are made with some related compounds.