Polycyclic Cage Structures as Lipophilic Scaffolds for Neuroactive Drugs

Abstract

Polycyclic cage scaffolds have been successfully used in the development of numerous lead compounds demonstrating activity in the central nervous system (CNS). Several neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, schizophrenia, and stroke, as well as drug abuse, can be modulated with polycyclic cage derivatives. These cage moieties, including adamantane and pentacycloundecane derivatives, improve the pharmacokinetic and pharmacodynamic properties of conjugated parent drugs and serve as an important scaffold in the design of therapeutically active agents for the treatment of neurological disorders. In this Minireview, we focus on the recent developments in the field of polycyclic cage compounds, as well as the relationship between the lipophilic character of these cage-derived drugs and the ability of such compounds to target and reach the CNS and improve the pharmacodynamic properties of compounds conjugated to it.

Tricycloundecane Derivatives as Potential N‐Methyl‐D‐aspartate (NMDA) Receptor and Voltage‐Gated Calcium Channel Modulators

“…In addition to their neuroprotective abilities, they are also useful scaffolds to conjugate to privileged structures for the purpose of improving their pharmacokinetic and pharmacodynamic profiles. [19] Polycyclic cages such as NGP1-01, ac losed-cage molecule (Figure 1), exhibits L-type VGCC blockage and NMDA receptor modulation. NGP1-01 wasa lso shown to be more potent than other polycyclic cages, such as the adamantanes, due to its characteristic dual inhibitory mechanism in attenuating calcium entry.T his distinct characteristic gives NGP1-01 an advantage over other potentialn europrotectivec ompounds as ad rug candidate in the prophylaxis and treatment of acute and chronic neurodegenerative disorders.…”

“…[18][19][20] The polycyclic compounds are uncompetitive NMDA receptor inhibitors with established neuroprotective properties and low toxicity profiles. These properties make them attractive for the development of new therapeutic agents in this field.…”

Alternative conditions for the synthesis of novel spiro[1,3-N,N-heterocyclic-adamantanes]

“…2 The 1-adamantyl group is crucial for the antiparasitic activity of 1,2,4-trioxane derivatives, 3 and replacement of the 2-(adamantan-1-yl)acetyl group with other hydrophobic moieties abolished the anti-EboV activity of a new class of antiviral dipeptides. 4 The incorporation of a spiroadamantane unit into 1,2,4-trioxanes 5 and 1,2,4,5-tetraoxanes 6 enhanced the antimalarial activity, together with low toxicity and high stability profiles both in vitro and in vivo.…”

Effect of Adamantyl Compounds on Dynamics of Spin Labelled Multilamellar Liposomes

“…1 Adamantane is characterised by its rigid and spherical structure 2 , possessing high lipophilicity. 3 It is well known that introducing an adamantyl moiety, with its unique physicochemical properties, into substances with known biological activity, improves their pharmacological properties and enhances their activity. 3,4 The synthesis of adamant-2-yl-tripeptides, which belong to the class of immunomodulating compounds comprising the elements of the bacterial peptidoglycan structures, was reported.…”