Synthesis and evaluation of aporphine analogs containing C1 allyl isosteres at the h5-HT2A receptor

Abstract

A series of C1 aporphine analogues related to compound 5 and that contain substituted allylic, alkynyl, nitrile, ester and benzyl groups was synthesized and evaluated for affinity at h5HT2A and α1A receptors in functional activity assays that measure calcium release. The presence of branched allylic substituent groups diminished affinity for the h5HT2A receptor. Likewise, the alkynyl, nitrile and ester derivatives evaluated displayed lower 5-HT2A receptor affinity as compared to 5. Hydrophobic, steric and electronic effects impact the affinity of p-substituted benzyl derivatives 8i – 8k but in different ways. High hydrophobicity and size favor 5-HT2A affinity whereas, high electronegativity disfavors 5-HT2A affinity. p-bromobenzyl analogue 8k was identified as a 5-HT2A receptor selective ligand, with the highest 5-HT2A receptor affinity of any aporphine known to date. Most of the other analogues were selective for the 5-HT2A versus the α1A receptor. ChemScore binding energies from docking studies correlated qualitatively with the observed trends in affinity for 8i - 8k, although the binding energies were not well differentiated quantitatively.

Pharmacological profiling an abundantly expressed schistosome serotonergic GPCR identifies nuciferine as a potent antagonist

“…Several aporphine compounds have previously been demonstrated to impair neuromuscular function in a variety of helminth parasites (Ayers et al., 2007, Chan et al., 2014, Lin et al., 2014), although the molecular target of these drugs in parasites is uncharacterized. The affinity of aporphinoids for mammalian 5-HT GPCRs (Munusamy et al., 2013, Ponnala et al., 2014, Ponnala et al., 2015, Farrell et al., 2016) was especially intriguing to us in this context. Here, we examine the action of four aporphinoid natural products at Sm.5HTR L and demonstrate a close correlation between receptor blockade and a hypomotive action on schistosome larvae and adults.…”

Synthesis and evaluation of nuciferine and roemerine enantiomers as 5-HT2and α1receptor antagonists

“…This in agreement with a previous study on analogues of nantenine which showed that variation of the alkoxy substituent at position C1 has a substantial effect on 5-HT 2A activity. [14][15][16] From the results for the α 1 receptors, (R)-nuciferine was the most potent compound at the α 1A and α 1B subtypes (pK b = 7.42 and 7.22, respectively), with 3-to 4-fold selectivity compared to the α 1D receptor. (R)-roemerine was the most potent compound at the α 1D subtype (pK b = 7.34) with 6-to 7-fold selectivity compared to the α 1A and α 1B receptors.…”

Identification of Novel 1-O-Substituted Aporphine Analogues as Potent 5-HT2C Receptor Agonists

“…Aporphines, a group of tetrahydroisoquinoline alkaloids, exhibit a wide range of CNS pharmacological activities represented by antiparkinsonian drug apomorphine, a dopamine D 2 agonist. − With regard to serotonin receptors, aporphines have mostly been studied as ligands for 5-HT 1A and 5-HT 2A receptors. ,,,− However, they are relatively unexplored as 5-HT 2C receptor ligands. Recently, our team discovered several aporphine derivatives as 5-HT 2C hit ligands by using thermal stability assay to screen a focused alkaloid library of more than 300 chemical components isolated from plants, e.g., (−)-crebanine [ 1 (Figure )] as a 5-HT 2C receptor antagonist with no selectivity over 5-HT 2A or 5-HT 2B .…”