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 morpholinecontaining 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.

Synthesis and In Vitro Activity of Novel Melphalan Analogs in Hematological Malignancy Cells

“…Thanks to this construction, this group can participate in lipophilic−hydrophilic interactions. Morpholine modulates properties of the overall structure, as the presence of a weak basic nitrogen at the opposite position of the oxygen atom enhances solubility [17]. Morpholine derivatives can act as antidepressants, analgesics, antitumor agents, antioxidants, antibiotics, or antifungals as well as serving in the treatment of central nervous system disorders [18].…”

Geminal Diheteroatomic Motifs: Some Applications of Acetals, Ketals, and Their Sulfur and Nitrogen Homologues in Medicinal Chemistry and Drug Design

“…Both drugs are comparable in efficacy for the treatment of mild to moderately severe hypertension; however, 112 elicited less orthostatic dizziness and diarrhea than 111. 59c Guanadrel (112) is partially metabolized by the liver to give 2-(2,3-dihydroxypropyl)guanidine (113), but nearly 50% of an orally administered dose appears as unchanged drug in the urine.…”

“…Although a morpholine heterocycle is only moderately basic (the conjugate acid of morpholine has a p K a value of 8.5, which is 2.6 units lower than for piperidine), it can function to stabilize acetals and ketals. Consequently, morpholine-based acetals have found utility in drug design, with the first application reported in 1996 as part of a search for orally bioavailable NK1 antagonists. ,− The lead piperidine-based NK1 antagonist 212 , although quite potent, suffered from poor oral bioavailability and exhibited a modest affinity for the L-type calcium channel, a potential liability for adverse cardiovascular effects . To address both issues, a significant effort was expended to reduce the basicity of the piperidine nitrogen atom, with two approaches proving to be effective: attachment of an electron-withdrawing heterocycle to the piperidine nitrogen atom linked through a methylene spacer and the introduction of an oxygen atom into the piperidine ring, a molecular edit that led to a morpholine acetal.…”

2-Oxa-5-azabicyclo[2.2.1]heptane as a Platform for Functional Diversity: Synthesis of Backbone-Constrained γ-Amino Acid Analogues

“…The morpholine ring system is a prominent component of a large number of medicinally relevant compounds. − It has been ranked in the top 20 most prevalent saturated nitrogen heterocycles in U.S. Food and Drug Administration-approved drugs . Replacing the morpholine motif with a constrained bridged morpholine resulted in marked improvements in selectivity and activity in a number of compounds. − There are also a number of patent claims for biologically active compounds with appended N-bonded bridged morpholines. − Carbon-bridged morpholines confer enhanced lipophilicity when attached to drug entities .…”

“…The introduction of an acetic acid unit on C-3 in the core motif A and further diversification with substituents of a stereodefined character would lead to novel oxazabicyclic γ-amino acids endowed with unique three-dimensional architectures . Incorporating stereogenic centers in molecules of potential biological interest imparts favorable properties, especially in the context of probing the three-dimensional space of enzymes and receptors. , Introducing a carboxylic acid group in conjunction with the secondary amine in A would constitute a new constrained γ-amino acid in the context of activities related to the CNS. ,,, …”