Occurrence of Morpholine in Central Nervous System Drug Discovery

Abstract

Developing drugs for the central nervous system (CNS) requires fine chemical modifications, as a strict balance between size and lipophilicity is necessary to improve the permeability through the blood-brain barrier (BBB). In this context, morpholine and its analogues represent valuable heterocycles, due to their conformational and physicochemical properties. In fact, the presence of a weak basic nitrogen atom and of an oxygen atom at the opposite position provides a peculiar pK_a value and a flexible conformation to the ring, thus allowing it to take part in several lipophilic-hydrophilic interactions, and to improve blood solubility and brain permeability of the overall structure. In CNS-active compounds, morpholines are used (1) to enhance the potency through molecular interactions, (2) to act as a scaffold directing the appendages in the correct position, and (3) to modulate pharmacokinetic/pharmacodynamic (PK/PD) properties. In this perspective, selected morpholine-containing CNS drug candidates are discussed to reveal the active pharmacophores accountable for the (1) modulation of receptors involved in mood disorders and pain, (2) bioactivity toward enzymes and receptors responsible for neurodegenerative diseases, and (3) inhibition of enzymes involved in the pathology of CNS tumors. The medicinal chemistry/pharmacological activity of morpholine derivatives is discussed, in the effort to highlight the importance of morpholine ring interactions in the active site of different targets, particularly reporting binding features retrieved from PDB data, when available.

Keywords: Alzheimer’s disease; Parkinson’s disease; blood-brain barrier; brain; cancer; enzyme inhibitor.

Figure 1

Approved morpholine-containing CNS drugs.

Figure 2

Neuroreceptors as molecular targets of morpholine-containing compounds.

Figure 3

Structure of endogenous cannabinoid receptor ligands, (−)-Δ⁹-THC and pravalodine. (b) Structure of a selective CB2 receptor agonist (compound 1) and antagonist (compound 2) and their interactions in the CB2 binding site (Adapted with permission from ref (39). Copyright (2017) American Chemical Society.).

Figure 4

Structure of sigma and serotonin receptor antagonists containing the N-morpholinoethyl moiety.

Figure 5

Crystal structure of the human neurokinin 1 receptor in complex with aprepitant (left) and detailed interactions with the receptor, viewed from the extracellular side above helix I (right, PDB: 6HLO).

Figure 6

Structure of a histamine H₃ receptor antagonist in comparison with the morpholine-containing analogue JNJ-10181457.

Figure 7

(a) Structure of first-generation mGlu2 NAMs and (b) structure of a morpholine-containing compound able to modulate the mGlu2 receptor.

Figure 8

Structure of (a) compounds able to modulate ionotropic receptors (GABA and NMDA receptors), in comparison with (b) morpholine-containing analogues.

Figure 9

Structure of morpholine-containing compounds able to modulate molecular targets involved in Parkinson’s disease, such as (a) LRRK2 kinase, (b) dopamine receptors, and (c) Nrf2 transcription factor.

Figure 10

(a) Structure of compound 13, and (b) its interactions within the active site of BACE-1 (PDB: 6BFX).

Figure 11

(a) Structure of compound 14 and key interactions within the active site of BACE-1 (PDB: 5CLM). (b) Lead optimization of compound 14 into compounds 15 and 16.

Figure 12

Structure of morpholine derivatives 17 and 18 developed as BACE-1 inhibitors.

Figure 13

Structure of morpholine-containing compounds involved in the reduction of amyloid β (Aβ) peptides for the treatment of Alzheimer’s disease by inhibiting γ-secretase or reducing Aβ42-induced cell toxicity.

Figure 14

(a) Structure of compound 22 and its interaction in the active site of δ-secretase (PDB: 5LUB); (b) structure of compound 23 and its interaction in the active site of δ-secretase (PDB: 5LUA).

Figure 15

Structure of (a) compounds able to modulate molecular targets (acetylcholinesterase enzyme (AChE), monoamine oxidase (MAO-A and MAO-B) and M1 acetylcholine receptor) involved in the regulation of several biogenic amines, in comparison with (b) morpholine-containing analogues.

Figure 16

(a) Structure of compound NVP-BKM120 and its interaction pattern in the active site of PI3Kγ (PDB: 3SD5). (b) Structure of compound PQR309 and its interaction pattern in the active site of PI3Kγ (PDB: 5OQ4).

Figure 17

Crystal structure of PI-103 in complex with mTOR (PDB: 4JT6).

Figure 18

Structure of morpholine-containing compounds able to selectively inhibit mTOR complex over the PI3K kinase family.