Neuropharmacological Potential of Diterpenoid Alkaloids

Abstract

This study provides a narrative review of diterpenoid alkaloids (DAs), a family of extremely important natural products found predominantly in some species of Aconitum and Delphinium (Ranunculaceae). DAs have long been a focus of research attention due to their numerous intricate structures and diverse biological activities, especially in the central nervous system (CNS). These alkaloids originate through the amination reaction of tetra or pentacyclic diterpenoids, which are classified into three categories and 46 types based on the number of carbon atoms in the backbone structure and structural differences. The main chemical characteristics of DAs are their heterocyclic systems containing β-aminoethanol, methylamine, or ethylamine functionality. Although the role of tertiary nitrogen in ring A and the polycyclic complex structure are of great importance in drug-receptor affinity, in silico studies have emphasized the role of certain sidechains in C13, C14, and C8. DAs showed antiepileptic effects in preclinical studies mostly through Na⁺ channels. Aconitine (1) and 3-acetyl aconitine (2) can desensitize Na⁺ channels after persistent activation. Lappaconitine (3), N-deacetyllapaconitine (4), 6-benzoylheteratisine (5), and 1-benzoylnapelline (6) deactivate these channels. Methyllycaconitine (16), mainly found in Delphinium species, possesses an extreme affinity for the binding sites of α7 nicotinic acetylcholine receptors (nAChR) and contributes to a wide range of neurologic functions and the release of neurotransmitters. Several DAs such as bulleyaconitine A (17), (3), and mesaconitine (8) from Aconitum species have a drastic analgesic effect. Among them, compound 17 has been used in China for decades. Their effect is explained by increasing the release of dynorphin A, activating the inhibitory noradrenergic neurons in the β-adrenergic system, and preventing the transmission of pain messages by inactivating the Na⁺ channels that have been stressed. Acetylcholinesterase inhibitory, neuroprotective, antidepressant, and anxiolytic activities are other CNS effects that have been investigated for certain DAs. However, despite various CNS effects, recent advances in developing new drugs from DAs were insignificant due to their neurotoxicity.

Keywords: Ranunculaceae; acetylcholine receptors; analgesics; anticonvulsants; antidepressive agents; dementia; diterpene alkaloids; neuropharmacology.

Scheme 1

Biological effects of DAs on CNS.

Figure 1

Backbone structures of different types of C18-diterpenoid alkaloids. Lappaconitines possess a methine at C7, while ranaconitines are characterized by an oxygen-containing group at this position. Ranaconitines have a methine unit at C4, while lappaconitines contain a methine unit or an oxygenated nonprotonated carbon, or chloro-substituents at C4.

Figure 2

The backbone structures of different types of C19-diterpenoid alkaloids.

Figure 3

The backbone structures of different types of C20-diterpenoid alkaloids.

Scheme 2

Biosynthetic pathway of diterpene alkaloids in Ranunculaceae.

Figure 4

The chemical structures of the anticonvulsant diterpene alkaloids.

Figure 5

(a) Chemical structure of methyllycaconitine; (b) Homomeric α7 nicotinic acetylcholine receptor.

Figure 6

Binding of methyllycaconitine could affect the binding pattern of ACh to binding sites and forms the three different conformational states. (a) The binding of two AChs to two consecutive binding sites leads to slow channel activation; (b) The binding of two AChs to two non-consecutive sites results in rapid activation and receptor desensitization; (c) Binding less than two AChs to binding sites causes a deactivation and the channel will be closed.

Figure 7

Chemical structures of the analgesic DAs.

Figure 8

Chemical structures of diterpene alkaloids with antidementia activity.

Figure 8

Chemical structures of diterpene alkaloids with antidementia activity.