Resolution and in Vitro and Initial in Vivo Evaluation of Isomers of Iodine-125-Labeled 1-Azabicyclo[2.2.2]oct-3-yl .alpha.-Hydroxy-.alpha.-(1-iodo-1-propen-3-yl)-.alpha.-phenylacetate: A High-Affinity Ligand for the Muscarinic Receptor

Abstract

1-Azabicyclo[2.2.2]oct-3-yl alpha-hydroxy-alpha-(1-iodo-1-propen-3-yl)- alpha-phenylacetate (IQNP, 1), is a highly selective ligand for the muscarinic acetylcholinergic receptor (mAChR). There are eight stereoisomers in the racemic mixture. The optical isomers of alpha-hydroxy-alpha-phenyl-alpha-(1-propyn-3-yl)acetic acid were resolved as the alpha-methylbenzylamine salts, and the optical isomers of 3-quinuclidinol were resolved as the tartrate salts. The E and Z isomers were prepared by varying the reaction conditions for the stannylation of the triple bond followed by purification utilizing flash column chromatography. In vitro binding assay of the four stereoisomers containing the (R)-(-)-3-quinuclidinyl ester demonstrated that each isomer of 1 bound to mAChR with high affinity. In addition, (E)-(-)-(-)-IQNP demonstrated the highest receptor subtype specificity between the m1 molecular subtype (KD, nM, 0.383 +/- 0.102) and the m2 molecular subtype (29.6 +/- 9.70). In vivo biodistribution studies demonstrated that iodine-125-labeled (E)-(-)-(+)-1 cleared rapidly from the brain and heart. In contrast, iodine-125-labeled (E)-(-)-(-)-, (Z)-(-)-(-)-, and (Z)-(-)-(+)-1 have high uptake and retention in mAChR rich areas of the brain. It was also observed that (E)-(-)-(-)-IQNP demonstrated an apparent subtype selectivity in vivo with retention in M1 (m1, m4) mAChR areas of the rain. In addition, (Z)-(-)-(-)-IQNP also demonstrated significant uptake in tissues containing the M2 (m2) mAChR subtype. These results demonstrate that the iodine-123-labeled analogues of the (E)-(-)-(-)- and (Z)-(-)-(-)-IQNP isomers are attractive candidates for single-photon emission-computed tomographic imaging of cerebral and cardiac mAChR receptor densities.

Chemogenomics knowledgebase and systems pharmacology for hallucinogen target identification—Salvinorin A as a case study

“…ACM2 got a docking score of 8.32. The molecular docking study was based on the co-crystal structure of ACM2 (PDB entry: 3UON, resolution 3.00 Å) published in 2012 (57, 58). The original ligand was QNB, an antagonist of ACM2 ( K d = 0.2nM).…”

“…Asp103, Tyr104, Ser107, Trp155, Phe181, Trp400, Tyr403, Asn404 and Cys429 were important residues within the binding pocket. The amine moiety of QNB formed a salt bridge (4.0 Å) with the side chain of Asp103 in TM3, which was proven to be important by modeling study, mutagenesis and covalent-labeling experiments (57, 58). Asn404 formed hydrogen bonds with both hydroxyl (2.6 Å) and carbonyl (3.2 A) group of QNB.…”

Imaging of Muscarinic Receptors in the Central Nervous System

“…In one approach, a ligand that is selective in vitro, AF-DX 116 [11-(((2-(diethylamino)-methyl)-1-piperidinyl) acetyl)-5-11-dihydro-6H-pyrido(2,3) (1,4) benzodiazepin-6-one], was modified to increase its BBB permeability while maintaining subtype selectivity [69]. In the second approach, non-subtype selective RS IQNB which crosses into the brain, was modified to increase its subtype selectivity [70,71]. Neither of these approaches has yielded a compound sensitive to changes in a subtype of the muscarinic receptor.…”

Muscarinic receptor agonists and antagonists

“…Although 17a may show M1 functional selectivity comparable to xanomeline, it is a less efficacious and potent M1 agonist than xanomeline. In the search for agents for the single-photon emission-computed tomography (SPECT) of cerebral and cardiac mAChR receptor densities, four stereoisomers of (R)-(-)-3-quinuclidinyl-α-hydroxy-α-(1-iodo-1-propen-3-yl)-α-phenylacetate IQNP (18) have been synthesised [22]. IQNP is an analogue of 4-IQNB (19), a high affinity muscarinic antagonist.…”

“…Several differently substituted phenylpropargyl oxime-ether incorporating the 1-azanorbornane ring (22) Table 4). The ability of the most selective compound (22b) and the parent oxime (22a) to stimulate PI accumulation or inhibit forskolin-stimulated accumulation of cAMP in CHO cells selectively expressing human m1 and m2 receptors was determined.…”