5‐Hydroxytryptamine_2A receptor binding activity of compounds from Litsea sessilis

Abstract

A 96-well microplate filtration based 5-HT(2A) receptor-radioligand binding assay was optimized and adopted to carry out a bioassay-guided fractionation of the methanol extract of the leaves of Litsea sessilis. This purification led to the isolation of two compounds identified as (+)-boldine (1) and (+)-dehydrovomifoliol (2). (+)-Boldine binds to 5-HT(2A) receptors at high concentrations with a K(i) value of 2.16 microm. However, (+)-dehydrovomifoliol showed minimal competitive inhibition on the binding of [(3)H]ketanserin to the same receptor with a K(i) value of 2.06 mm. These results suggest that (+)-boldine influences the activity of 5-HT(2A) receptors through competitive binding as an agonist or antagonist.

Structure‐Based Identification of Aporphines with Selective 5‐HT2A Receptor‐Binding Activity

“…Because boldine has been previously identified in our research as having significant 5‐HT 2A receptor‐binding activity (16), 52 ligands were selected from the ZINC database (18) on the basis of having at least 90% similarity to the boldine structure, that is, with a Tanimoto coefficient ≥90%, were purchasable and had drug‐like properties (37,38), that is, with molecular weight of 150–500 kDa, xlog p ≤ 5, number of rotatable bonds ≤8, polar surface area ≤150 Å 2 and number of H‐bond acceptors ≤10. Ligands with unusual substituents that are not found in naturally occurring aporphines, that is, those containing a methylamino or a hydroxymethyl substituent at the C3 position or a dimethylamino group at the C6 position, were excluded.…”

“…All assays were performed in triplicate in a total volume of 250 μL according to the methods published previously (16,24–26) with minor modifications. Two hundred μL of either striatum [30 μg/well (D 1 ) and 50 μg/well (D 2 )] or cerebral cortex [100 μg/well (5‐HT 1A and 5‐HT 2A )] was incubated with 25 μL of radioligand [0.5 n m [ 3 H] SCH 23390 (D 1 ), 0.8 n m [ 3 H] spiperone (D 2 ), 0.4 n m [ 3 H] 8‐OH‐DPAT (5‐HT 1A ) or 0.5 n m [ 3 H] ketanserin (5‐HT 2A )] and 25 μL of the test compound (at 9–12 varied concentrations).…”

“…However, there have been relatively few reports of aporphines being found to have activity at 5‐HT 2A receptors (10–15). Following the recent discovery in our research group that ( S )‐boldine possesses significant 5‐HT 2A receptor‐binding activity ( K i = 2160 n m ) (16), we decided to investigate whether other naturally occurring aporphines might also be active against this receptor target, using a combination of in silico and in vitro screening approaches. A series of aporphines were docked into a 5‐HT 2A homology model derived from our previous work (17).…”

Aporphine Alkaloids: A Kind of Alkaloids’ Extract Source, Chemical Constitution and Pharmacological Actions in Different Botany

“…-H Phoebe grandis [116] Lindera aggregate [117] Litsea sessilis [118] Lindera angustifolia [46] Cassytha filiformis [119] Peumus boldus Mol. [120] Litsea wightiana [103] Lindera aggregate-Kosterm [121] Norpredicentrine -OCH 3 -OH -H -H -H -OCH 3 -OCH 3 -H Lindera fragrans O-liv.…”

Chemical Constituents of Plants from the Genus Litsea

“…About 54 alkaloids, i.e., 6 -59, have been characterized from this genus [6 -41]. The highest numbers of alkaloids (23) 2.7. Triterpenoids.…”