(-)-Stepholidine blocks expression, but not development, of cocaine conditioned place preference in rats

Bennett, Andrew F.; Barrera, Eddy D.; Krishna, Namballa Hari; Harding, Wayne W.; Ranaldi, Robert

doi:10.1016/j.neulet.2020.135151

Cited by 4 publications

(4 citation statements)

References 51 publications

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“…We have evaluated analogues of 1,2,9,10-tetraoxygenated THPB (−)-stepholidine ( 2 ), which is known as a D1R/D2R/D3R antagonist and which we and others have found to display anti-addictive and antipsychotic effects in vivo. − Our structure–activity relationship (SAR) studies revealed that homologation of the methyl group at the C-9 position allows for the retention of high D1R affinity . We also found that bromination at the C-12 position tends to increase D1R affinity.…”

Section: Introductionmentioning

confidence: 99%

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

Namballa,

Dorogan,

Gudipally

et al. 2023

J. Med. Chem.

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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 12a and 12b, with nanomolar affinities for D1R and no affinity for either D2R or D3R, with compound 12a being identified as a D1R antagonist for both G-protein- and β-arrestin-based signaling. Compound 23b was identified as the most potent and selective D3R ligand containing a THPB template to date and functions as an antagonist for both G-protein- and β-arrestin-based signaling. Molecular docking and molecular dynamics studies validated the D1R and D3R affinity and selectivity of 12a, 12b, and 23b.

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Section: Introductionmentioning

confidence: 99%

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

Namballa,

Dorogan,

Gudipally

et al. 2023

J. Med. Chem.

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“…Disturbances in dopaminergic neurotransmission have significant implications for neurological disorders such as Parkinson’s disease, schizophrenia and psychostimulant disorders. There is a current interest in the deployment of selective D1R full agonists/partial agonists to treat these conditions [ 16 , 17 , 18 , 19 , 20 , 21 ]. Classical D1R agonists contain a catechol motif that is associated with suboptimal pharmacokinetic properties, including diminished blood-brain barrier penetration and poor oral bioavailability.…”

Section: Introductionmentioning

confidence: 99%

“…Molecules 2023, 28, 6010 2 of 17 disorders. There is a current interest in the deployment of selective D1R full agonists/partial agonists to treat these conditions [16][17][18][19][20][21]. Classical D1R agonists contain a catechol motif that is associated with suboptimal pharmacokinetic properties, including diminished bloodbrain barrier penetration and poor oral bioavailability.…”

Section: Introductionmentioning

confidence: 99%

“…20 (d, J = 8.6 Hz, 1H),6.01 (td, J = 17.1, 7.0 Hz, 1H), 5.55 (s, 1H), 5.53-5.48 (m, 1H), 4.72 (d, J = 10.1 Hz, 1H), 3.85-3.76 (m, 3H), 3.67-3.65 (m, 1H), 3.52-3.43 (m, 3H), 3.02-2.94 (m, 1H), 2.34 (s, 3H) ppm 13. C NMR (100 MHz, DMSO-d6) δ 152.4, 141.2, 138.6, 137.1, 134.9, 129.4, 129.3, 128.4, 127.9, 127.7, 126.7, 125.9, 120.4, 114.4, 59.8, 58.1, 51.8, 44.3, 26.7, 21.5 ppm.…”

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confidence: 99%

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

Giri,

Namballa,

Emogaje

et al. 2023

Molecules

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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.

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

Namballa,

Decker,

Dorogan

et al. 2023

Bioorganic Chemistry

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(-)-Stepholidine blocks expression, but not development, of cocaine conditioned place preference in rats

Cited by 4 publications

References 51 publications

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

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

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

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

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