Design, Synthesis, and Biological Characterization of Bivalent 1-Methyl-1,2,5,6-tetrahydropyridyl-1,2,5-thiadiazole Derivatives as Selective Muscarinic Agonists

Abstract

Selective muscarinic agonists could be useful in the treatment of neurological disorders such as Alzheimer's disease, schizophrenia, and chronic pain. Many muscarinic agonists have been developed, yet most exhibit at best limited functional selectivity for a given receptor subtype perhaps because of the high degree of sequence homology within the putative binding site, which appears to be buried within the transmembrane domains. Bivalent compounds containing essentially two agonist pharmacophores within the same molecule were synthesized and tested for receptor binding affinity and muscarinic agonist activity. A series of bis-1,2,5-thiadiazole derivatives of 1,2,5,6-tetrahydropyridine linked by an alkyloxy moiety exhibited very high affinity (K(i) < 1 nM) and strong agonist activity. The degree of activity depended on the length of the linking alkyl group, which could be replaced by a poly(ethylene glycol) moiety, resulting in improved water solubility, binding affinity, and agonist potency.

Synthesis and Biological Evaluation of Bivalent Ligands for the Cannabinoid 1 Receptor

“…Indeed, significant progress has been made in a number of GPCRs including opioids, 13, 15 adrenergic, 16, 17 dopamine, 18 serotonin 19, 20 and muscarinic receptors. 21, 22 Most significantly, much success has been recently achieved by Portoghese and co-workers with bivalent opioid ligands in vivo . 42, 43 In particular, μ-opioid (MOP) agonist/δ-opioid (DOP) antagonist bivalent ligands were shown to be potent analgesics after systemic administration, but did not produce the tolerance or dependence seen with traditional monovalent opioid analgesics.…”

In Vivo Characterization of (−)(−)MCL-144 and (+)(−)MCL-193: Isomeric, Bivalent Ligands with Mu/Kappa Agonist Properties

“…Bivalent ligands have been synthesized to target many different GPCRs including the: serotonin (18), muscarinic (19), and adrenergic (20) receptors. Additionally, the design and synthesis of bivalent ligands has been successfully applied within the opioid field, yielding the important κ antagonist, nor-BNI (21) along with new pharmacological tools, such as KDN21, an antagonist ligand for the heterodimerized δ and κ receptors (22).…”

Towards the development of new subtype-specific muscarinic receptor radiopharmaceuticals — Radiosynthesis and ex vivo biodistribution of [18F]3-(4-(2-(2-(2-fluoroethoxy)ethoxy)ethylthio)-1,2,5-thiadiazol-3-yl)-1-methyl-1,2,5,6-tetrahydropyridine

“…Several TZTP derivatives with incorporated PEG groups have been synthesized in attempts to achieve subtype selectivity and improve water solubility, binding affinity, and agonist potency toward mAChRs. 27,28 The present work further explores the use of PEG groups as a means of expanding the series of TZTP derivatives, by replacing alkyl groups with PEG chains; [ 18 F]fluoro-PEG groups have demonstrated similar pharmacological advantages when incorporated into PET radiopharmaceuticals. 29 In preparation for in vitro binding assay studies, all 19 TZTP analogs synthesized in the present work (Table 1) were characterized by 1 H and 19 F (when applicable) NMR spectroscopy, high resolution mass spectrometry, and elemental analysis (all compounds were >97% pure by elemental analysis).…”