Chemistry and Behavioral Studies Identify Chiral Cyclopropanes as Selective α4β2-Nicotinic Acetylcholine Receptor Partial Agonists Exhibiting an Antidepressant Profile

Abstract

Despite their discovery in the early 20th century and intensive study over the last twenty years, nicotinic acetylcholine receptors (nAChRs) are still far from being well understood. Only a few chemical entities targeting nAChRs are currently undergoing clinical trials, and even fewer have reached the marketplace. In our efforts to discover novel and truly selective nAChR ligands, we designed and synthesized a series of chiral cyclopropane-containing α4β2-specific ligands that display low nanomolar binding affinities and excellent subtype selectivity, while acting as partial agonists at α4β2-nAChRs. Their favorable antidepressant-like properties were demonstrated in the classical mouse forced swim test. Preliminary ADMET studies and broad screening towards other common neurotransmitter receptors were also carried out to further evaluate their safety profile and eliminate their potential off-target activity. These highly potent cyclopropane ligands possess superior subtype selectivity compared to other α4β2-nAChR agonists reported to date, including the marketed drug varenicline, and therefore may fully satisfy the crucial prerequisite for avoiding adverse side effects. These novel chemical entities could potentially be advanced to the clinic as new drug candidates for treating depression.

The “Cyclopropyl Fragment” is a Versatile Player that Frequently Appears in Preclinical/Clinical Drug Molecules

“…143 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 40 The (1S,2R)-cyclopropane side chain at the 5-position of the pyridine scaffold is critical for achieving exceptional α4β2-nAChR subtype selectivity. Consequently, Onajole and coworkers 147 inserted a (1S,2R)-configured cyclopropane side chain at the 5-position of their Npyridyldiazabicyclo[3.3.0]octane motif, a move that eventually led to the discovery of compound 116, showing a 1600-fold selectivity for α4β2 over α3β4-nAChR as shown in Figure 48.…”

Insights into the Structural Determinants Required for High-Affinity Binding of Chiral Cyclopropane-Containing Ligands to α4β2-Nicotinic Acetylcholine Receptors: An Integrated Approach to Behaviorally Active Nicotinic Ligands

“…Successive hydrogenation of the terminal double bond and removal of the Boc group smoothly gave the target compound 10 as its trifluoroacetate salt. For the fluorine-containing analogs, the starting alcohol 11 16 was tosylated followed by reaction with n -tetrabutylammonium fluoride. Boc deprotection of the resulting fluoride yielded compound 12 as its trifluoroacetate salt.…”

Synthesis and biological evaluation of novel hybrids of highly potent and selective α4β2-Nicotinic acetylcholine receptor (nAChR) partial agonists

“…1,3-Dibromopyridine ( 9 ) was advanced to the optically pure chiral intermediates 16 and 17 according to published methods[9]. Thus, one of the bromine atoms was replaced by a benzyloxy group to obtain compound 10 which underwent a Heck reaction with n -butyl acrylate to afford the α,β-unsaturated ester 11 .…”

“…Besides α4, β2, or α7, other unidentified subunits may also be present. Details are provided in the Experimental Section. c K i values for nicotine are taken from the PDSP Assay Protocol Book. d ND: not detected. e NA: not active, defined as < 50% inhibition of binding in the primary assay at 10 μM. f K i values for 3, 4, and 1 are from the literature[8, 9]. …”