Tetrahydroprotoberberine alkaloids with dopamine and σ receptor affinity

Abstract

Two series of analogues of the tetrahydroprotoberberine (THPB) alkaloid (±)-stepholidine that a) contain various alkoxy substituents at the C10 position and, b) were de-rigidified with respect to (±)-stepholidine, were synthesized and evaluated for affinity at dopamine and σ receptors in order to evaluate effects on D3 and σ2 receptor affinity and selectivity. Small n-alkoxy groups are best tolerated by D3 and σ2 receptors. Among all compounds tested, C10 methoxy and ethoxy analogues (10 and 11 respectively) displayed the highest affinity for σ2 receptors as well as σ2 versus σ1 selectivity and also showed the highest D3 receptor affinity. De-rigidification of stepholidine resulted in decreased affinity at all receptors evaluated; thus the tetracyclic THPB framework is advantageous for affinity at dopamine and σ receptors. Docking of the C10 analogues at the D3 receptor, suggest that an ionic interaction between the protonated nitrogen atom and Asp110, a H-bond interaction between the C2 phenol and Ser192, a H-bond interaction between the C10 phenol and Cys181 as well as hydrophobic interactions of the aryl rings to Phe106 and Phe345, are critical for high affinity of the compounds.

Synthesis and evaluation of C9 alkoxy analogues of (-)-stepholidine as dopamine receptor ligands

“…Furthermore, there is a paucity of SAR information concerning the impact of structural modification of THPBs in general (including stepholidine) in relation to affinity and activity at D3 receptors. 31 Halogen atoms can provide significant gains in receptor affinity to a scaffold. 32 Although the presence of a C12 chloro group affords high D1 receptor affinity in the case of 12-chloroscoulerine ( 5 ), the effect of the presence of a bromo group at C12 of stepholidine analogues on D1, D2 and D3 affinity, has not been assessed up to now.…”

Deep Learning in Drug Discovery and Medicine; Scratching the Surface

“…Olivercona et al [ 54 ] developed a sequence-based generative model for molecular de novo design and have illustrated its application in predicting molecules with specified desirable properties. Another strategy employed by this group includes various types of autoencoder models that rendered new structures that were predicted to be active against dopamine type receptor 2 [ 55 , 56 , 57 , 58 ]. Even pharmaceutical giants such as Bayer Healthcare and Roche have attributed their recent success in developing optimized pharmacophores to computer-assisted drug design technologies [ 59 , 60 ].…”

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

“…[8] THPBs such as (S)-stepholidine, (S)-isocorypalmine, (S)-govadine, and (S)-tetrahydropalmatine ( Figure 1) have featured in several studies investigating their bioactivities as dopamine receptor ligands. [9][10][11][12][13][14] There are five subtypes of dopamine receptor (D 1 R-D 5 R) and these are grouped into two families: D 1 -like and D 2 -like based on differences in signal transduction mechanisms and structure. The D 1 -like family includes the structurally related D 1 R and D 5 R subtypes, while the D 2 -like family is represented by D 2 R-D 4 R. [15] Structure-activity relationship (SAR) studies to date indicate that THPBs exert a preference for binding to D 1 -like receptors although several compounds also display good affinity for D 2 -like receptors.…”

“…[12,14,[17][18][19][20][21][22][23][24][25] Our lab recently discovered a number of THPBs with strong D 1 R affinity (ranging in K i values from 6 to 40 nM) and strong σ 2 receptor (σ 2 R) affinity (ranging in K i values from 1 to 107 nM). [10] The σ 2 R is highly expressed in a number of cancers and has been targeted for both cancer diagnosis and cancer therapy. [26][27][28][29][30] Within the central nervous system (CNS) realm, the related σ 1 receptor (σ 1 R) is known to play a role in depression, addiction and schizophrenia (among other neuropsychiatric disorders).…”