Tacrine Derivatives in Neurological Disorders: Focus on Molecular Mechanisms and Neurotherapeutic Potential

Abstract

Tacrine is a drug used in the treatment of Alzheimer's disease as a cognitive enhancer and inhibitor of the enzyme acetylcholinesterase (AChE). However, its clinical application has been restricted due to its poor therapeutic efficacy and high prevalence of detrimental effects. An attempt was made to understand the molecular mechanisms that underlie tacrine and its analogues influence over neurotherapeutic activity by focusing on modulation of neurogenesis, neuroinflammation, endoplasmic reticulum stress, apoptosis, and regulatory role in gene and protein expression, energy metabolism, Ca²⁺ homeostasis modulation, and osmotic regulation. Regardless of this, analogues of tacrine are considered as a model inhibitor of cholinesterase in the therapy of Alzheimer's disease. The variety both in structural make-up and biological functions of these substances is the main appeal for researchers' interest in them. A new paradigm for treating neurological diseases is presented in this review, which includes treatment strategies for Alzheimer's disease, as well as other neurological disorders like Parkinson's disease and the synthesis and biological properties of newly identified versatile tacrine analogues and hybrids. We have also shown that these analogues may have therapeutic promise in the treatment of neurological diseases in a variety of experimental systems.

Figure 1

Illustration of compounds of tacrine analogues. The compound number denoted by (1) 9-Amino-2,3-dihydro-1H-cyclopenta[1,2-b]quinoline. (2) 11-Amino-2,3,4,5-tetrahydro-1H-cyclohepta[1,2-b]quinoline. (3) 12-Amino-1,2,3,4,5,6-hexahydrocycloocta[1,2-b]quinoline. (4) 9-Amino-1,4-methano-1,2,3,4-tetrahydroacridine. (5) 9-Amino-1,4-methano-1,2,3,4-tetrahydro-4,11,11-trimethylacridine. (6) 6-Amino-4,5-benzo-5H-cyclopenta[1,2-b]quinoline. (7) 9-Amino-5,6,7,8-tetrahydroquinolino[3,2-e]-1-benzazocine. (8) Ethyl 4-(1-acetyl-1H-pyrrol-2-yl)-5-amino-6,7,8,9- tetrahydro-2-methyl-4H-pyran[2,3-b]quinoline-3-carboxylate. (9) Ethyl 5-amino-6,7,8,9-tetrahydro-2-methyl-4-(4- pyridyl)-benzo[b][1–8]naphthyridine-3-carboxylate. (10) 9-amino-6-chloro-2,3-dihydro-[1H] cyclopenta [1,2-b]-quinoline. (11) 5-Amino-2-(dimethylamino)-6,7,8,9-tetrahydrobenzo[1,8-b]-naphthyridine-3-carbonitrile. (12) 5-Amino-2-(prop-2-yn-1-ylamino)-6,7,8,9-tetrahydrobenzo[1,8-b]-naphthyridine-3-carbonitrile. (13) 5-Amino-2-(methyloxy)-6,7,8,9-tetrahydrobenzo[1,8-b]-naphthyridine-3-carbonitrile. (14) 5-Amino-2-chloro-6,7,8,9-tetrahydrobenzo[1,8-b]- naphthyridine-3-carbonitrile. (15) 5-Amino-7-benzyl-2-methoxy-6,7,8,9- tetrahydropyrido[2,3-b][1,6]naphthyridine-3-carbonitrile. (16) 5-Amino-7-benzyl-2-chloro-6,7,8,9- tetrahydropyrido[2,3-b][1,6]naphthyridin-3-carbonitrile. (17) Bis(7)tacrine dimer. (18) Cystamine-tacrine dimer. (19) Nontoxic tacrine-organic nitrates, compound E (as the name wasn't found in the paper). (20) N-(7-Oxo-7H-dibenzo[de,h]quinolin-9-yl)-3-((2-((1,2,3,4-tetrahydroacridin-9-yl)amino)ethyl)amino)propanamide. (21) N1-(2-(Dimethylamino)benzyl)-N9-(1,2,3,4-tetrahydroacridin-9-yl)nonane-1,9-diamine. (22) N-alkyl-7-methoxytacrine.

Figure 2

Illustration of compounds for neuropharmacological potential of tacrine hybrids.

Figure 3

Illustration representing the site of action of different tacrine derivatives in Alzheimer's disease.

Figure 4

Illustration representing the site of action of different tacrine derivatives in Parkinson's disease.