Natural Product-Inspired Dopamine Receptor Ligands.

Due to their evolutionary bias as ligands for biologically relevant drug targets, natural products offer a unique opportunity as lead compounds in drug discovery. Given the involvement of dopamine receptors in various physiological and behavioral functions, they are linked to numerous diseases and disorders such as Parkinson's disease, schizophrenia, and substance use disorders. Consequently, ligands targeting dopamine receptors hold considerable therapeutic and investigative promise.

Fluoroalkoxylated C-3 and C-9 (S)-12-bromostepholidine analogues with D1R antagonist activity.

To illuminate the tolerance of fluoroalkoxylated groups at the C-3 and C-9 positions of tetrahydroprotoberberines (THPBs) on D1R activity, C-3 and C-9 fluoroalkoxylated analogues of (S)-12-bromostepholidine were prepared and evaluated. All compounds examined were D1R antagonists as measured by a cAMP assay. Our structure-activity studies herein indicate that the C-3 position tolerates a 1,1-difluoroethoxy substituent for D1R antagonist activity.

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, -3, C-3' and C-4' positions.

Discovery of Selective Dopamine Receptor Ligands Derived from (-)-Stepholidine via C-3 Alkoxylation and C-3/C-9 Dialkoxylation.

We evaluated C-3 alkoxylated and C-3/C-9 dialkoxylated (-)-stepholidine analogues to probe the tolerance at the C-3 and C-9 positions of the tetrahydroprotoberberine (THPB) template toward affinity for dopamine receptors. A C-9 ethoxyl substituent appears optimal for D1R affinity since high D1R affinities were observed for compounds that contain an ethyl group at C-9, with larger C-9 substituents tending to decrease D1R affinity. A number of novel ligands were identified, such as compounds and , with nanomolar affinities for D1R and no affinity for either D2R or D3R, with compound being identified as a D1R antagonist for both G-protein- and β-arrestin-based signaling.

End-to-end sequence-structure-function meta-learning predicts genome-wide chemical-protein interactions for dark proteins.

Systematically discovering protein-ligand interactions across the entire human and pathogen genomes is critical in chemical genomics, protein function prediction, drug discovery, and many other areas. However, more than 90% of gene families remain "dark"-i.e.

Semisynthetic Transformations on (+)-Boldine Reveal a 5-HTR Antagonist.

Aporphine alkaloids have shown affinity for serotonin receptors (5-HTRs), and there has been a recent upsurge of interest in aporphines as 5-HTR ligands. 1,2,9,10-Tetraoxygenated aporphine alkaloids in particular have demonstrated good affinity for 5-HTRs. In continued efforts to understand the impacts of structural modification of the 1,2,9,10-tetraoxygenated aporphine template on affinity, selectivity, and activity at 5-HTR subtypes, we used (+)-boldine () as a semisynthetic feedstock in the preparation of C-2-alkoxylated (+)-predicentrine analogues.

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.

MeAl-mediated domino nucleophilic addition/intramolecular cyclisation of 2-(2-oxo-2-phenylethyl)benzonitriles with amines; a convenient approach for the synthesis of substituted 1-aminoisoquinolines.

A simple and efficient protocol for the construction of 1-aminoisoquinolines was achieved by treating 2-(2-oxo-2-phenylethyl)benzonitriles with amines in the presence of MeAl. The reaction proceeds via a domino nucleophilic addition with subsequent intramolecular cyclisation. This method provides a wide variety of substituted 1-aminoisoquinolines with good functional group tolerance.

β-Carboline tethered cinnamoyl 2-aminobenzamides as class I selective HDAC inhibitors: Design, synthesis, biological activities and modelling studies.

The effect of β-carboline motif as cap for HDAC inhibitors containing cinnamic acid as linker and benzamides as zinc binding group was examined in this study. A series of β-carboline-cinnamide conjugates have been synthesized and evaluated for their HDAC inhibitory activity and in vitro cytotoxicity against different human cancer cell lines. Almost all the compounds exhibited superior HDAC inhibitory activity than the standard drug Entinostat for in vitro enzymatic assay.

First synthesis of thiazepino[3,4-a]isoquinolines, a facile new synthetic route to diazepino[3,4-a]isoquinolines and assessment of their dopamine and σ receptor affinities.

Heterocycles that bear the novel 5,6,14,14a-tetrahydro-8H-benzo[6,7][1,4] thiazepino[3,4-a]isoquinoline and the 5,6,14,14a-tetrahydro-8H-13l2-benzo [6,7][1,4]diazepino[3,4-a]isoquinoline frameworks were synthesized in a facile manner. These tetrahydroprotoberberine (THPB)-inspired scaffolds demonstrate selective affinity for the σR in contrast to the naturally occurring THPB congeners that show DR and σR selectivity.

New tetrahydroisoquinoline-based DR ligands with an o-xylenyl linker motif.

The effect of rigidification of the n-butyl linker region of tetrahydroisoquinoline-containing DR ligands via inclusion of an o-xylenyl motif was examined in this study. Generally, rigidification with an o-xylenyl linker group reduces DR affinity and negatively impacts selectivity versus DR for compounds possessing a 6-methoxy-1,2,3,4,-tetrahydroisoquinolin-7-ol primary pharmacophore group. However, DR affinity appears to be regulated by the primary pharmacophore group and high affinity DR ligands with 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline and 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline primary pharmacophore groups were identified.

Structural manipulation of aporphines via C10 nitrogenation leads to the identification of new 5-HTR ligands.

Aporphine alkaloids containing a C10 nitrogen motif were synthesized and evaluated for affinity at 5-HTR, 5-HTR, 5-HTR and 5-HTR. Three series of racemic aporphines were investigated: 1,2,10-trisubstituted, C10 N-monosubstituted and compounds containing a C10 benzofused aminothiazole moiety. The 1,2,10-trisubstituted series of compounds as a group displayed modest selectivity for 5-HTR and also had moderate 5-HTR affinity.

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 DR, DR and DR. As is typical of the 1-phenylbenzazepine scaffold, the compounds displayed selectivity towards DR and DR; analogs generally lacked affinity for DR. Interestingly, 2',6'-dichloro substituted analogs showed modest DR versus DR selectivity whereas this selectivity was reversed in compounds with a 2'-halo substitution pattern.

Identification of C10 nitrogen-containing aporphines with dopamine D versus D receptor selectivity.

New aporphines containing C10 nitrogen substituents (viz. nitro, aniline or amide moieties), were synthesized and evaluated for affinity at human serotonin 5-HT and 5-HT receptors and at human dopamine D, D and D receptors. Two series of analogs were investigated: series A which contain a sole C10 nitrogen substituent on the tetracyclic aporphine core and series B which are 1,2,10-trisubstituted aporphines.

Iodine promoted dual oxidative C(sp)-H amination of 2-methyl-3-arylquinazolin-4(3H)-ones: a facile route to 1,4-diarylimidazo[1,5-a]quinazolin-5(4H)-ones.

An iodine promoted tandem oxidative condensation of benzylamines and 2-methylquinazolin-4-(3H)-ones was developed to yield imidazo[1,5-a]quinazolin-5(4H)-ones via dual C(sp)-H amination under metal free conditions in a greener way using molecular oxygen as a terminal oxidant. This tandem transformation provides an efficient approach to construct various functionalized imidazo[1,5-a]quinazolin-5(4H)-ones in a straightforward manner via a sequential amination-oxidation-annulation-aromatisation.