Synthesis and Biological Characterization of 1,4,5,6-Tetrahydropyrimidine and 2-Amino-3,4,5,6-tetrahydropyridine Derivatives as Selective m1 Agonists

Abstract

Previous studies identified several novel tetrahydropyrimidine derivatives exhibiting muscarinic agonist activity in rat brain. Such compounds might be useful in treating cognitive and memory deficits associated with low acetylcholine levels, as found in Alzheimer's disease. To determine the molecular features of ligands important for binding and activity at muscarinic receptor subtypes, the series of tetrahydropyrimidines was extended. Several active compounds were examined further for functional selectivity through biochemical studies of muscarinic receptor activity using receptor subtypes expressed in cell lines. Several amidine derivatives displayed high efficacy at m1 receptors and lower activity at m3 receptors coupled to phosphoinositide (PI) metabolism in A9 L cells. Four ligands, including 1b, 1f, 2b, and 7b, exhibited marked functional selectivity for m1 vs m3 receptors. Compound 1f also exhibited low activity at m2 receptors coupled to the inhibition of adenylyl cyclase in A9 L cells. Molecular modeling studies also were initiated to help understand the nature of the interaction of muscarinic agonists with the m1 receptor using a nine amino model of the m1 receptor. Several important interactions were identified, including interactions between the ester moiety and Thr192. Additional interactions were found for oxadiazoles and alkynyl derivatives with Asn382, suggesting that enhanced potency and selectivity may be achieved by maximizing interactions with Asp105, Thr192, and Asn382. Taken together, the data indicate that several amidine derivatives display functional selectivity for m1 muscarinic receptors, warranting further evaluation as therapeutic agents for the treatment of Alzheimer's disease. In addition, several amino acid residues were identified as potential binding sites for m1 agonists. These data may be useful in directing efforts to develop even more selective m1 agonists.

Fluorinated heterocyclic compounds: an assay on the photochemistry of some fluorinated 1-oxa-2-azoles: an expedient route to fluorinated heterocycles

“…On the basis of the above photoreactivities, we now looked at the photochemical behavior of some fluorinated 1,2,4-oxadiazoles. In this context, we wish to note that in the last years, 1,2,4-oxadiazole derivatives have been receiving much attention by virtue of their pharmaceutical applications [32][33][34][35][36][37][38][39][40]. In this paper, we will consider the photochemistry of 3-amino-5-perfluoroalkyl-and 3-amino-5-polyfluorophenyl-1,2,4-oxadiazoles in view of developing methodologies for the synthesis of the corresponding fluorinated ring isomers, namely the 1,3,4-oxadiazoles.…”

Development, Scope and Mechanisms of Multicomponent Reactions of Asymmetric Electron‐Deficient Alkynes with Amines and Formaldehyde

“…[10] Because of the wide range of applications of pyrimidines in pharmaceutical research, such as muscarinic agonist activity, [11] protein-nucleic acid interactions, [12] antiviral activity [13] and inflammatory activity, [14] the development of efficient methods for their synthesis has continuously attracted the attention of many chemists. In modern organic synthesis, the hexahydropyrimidine nucleus has been employed as a protecting group in selective acylations and additions of 1,3-diamines owing to its easy cleavage in mildly acidic media.…”

Synthesis of 1,2,4-oxadiazole-linked orthogonally urethane-protected dipeptide mimetics

“…2 Several types of non-natural linkages such as retro-amides, ureas, 3 carbamates, 4 sulfonamides, 5 thiazoles and 6 triazoles, 7,8 are used as amide bond replacements to obtain new classes of peptidomimetics with considerable success. 1,2,4-Oxadiazoles 9 are important amongst biologically active heterocycles, the utility of which has been extended to many potent classes of drug-related molecules such as ligands of benzodiazepine receptors, 10 muscuranic receptor agonists, 11 antiviral compounds, angiotensin II receptor antagonists 12 and HIV-1 reverse transcriptase inhibitors. 13 In peptide chemistry, this group has been studied mainly as an efficient amide and ester bond bioisoester.…”