Chemical factors influencing the psychotomimetic potency of glycolate esters

Baumgold, Jesse; Abood, Leo G.; Hoss, Wayne

doi:10.1016/0024-3205(75)90097-1

Cited by 7 publications

(4 citation statements)

References 9 publications

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confidence: 85%

“…Our lead molecule in this study, PBB, was reported along with a series of psychotomimetic glycolate esters by Baumgold et al in 1975 . Evaluation of the described structure–activity relationship on this scaffold indicated that substitution of one of the phenyls with a cyclopentyl group resulted in a reduction in affinity toward mACh . Although only racemic mixtures were evaluated in the original publication, the substitution of a phenyl with a cyclopentyl group was considered attractive since it would introduce an additional stereocenter.…”

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confidence: 99%

“…9 Evaluation of the described structure−activity relationship on this scaffold indicated that substitution of one of the phenyls with a cyclopentyl group resulted in a reduction in affinity toward mACh. 9 Although only racemic mixtures were evaluated in the original publication, the substitution of a phenyl with a cyclopentyl group was considered attractive since it would introduce an additional stereocenter. The chemistry would thus provide four stereomers that could be evaluated against PBB for muscarinic receptor in vitro affinity.…”

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confidence: 99%

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Discovery of a Novel Muscarinic Receptor PET Radioligand with Rapid Kinetics in the Monkey Brain

Malmquist

Varnäs

Svedberg

et al. 2017

ACS Chem. Neurosci.

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Positron emission tomography (PET), together with a suitable radioligand, is one of the more prominent methods for measuring changes in synaptic neurotransmitter concentrations in vivo. The radioligand of choice for such measurements on the cholinergic system is the muscarinic receptor antagonist N-[1-C]propyl-3-piperidyl benzilate (PPB). In an effort to overcome the shortcomings with the technically cumbersome synthesis of [C]PPB, we designed and synthesized four structurally related analogues of PPB, of which (S,R)-1-methylpiperidin-3-yl)2-cyclopentyl-2-hydroxy-2-phenylacetate (1) was found to bind muscarinic receptors with similar affinity as PPB (3.5 vs 7.9 nM, respectively). (S,R)-1 was radiolabeled via N-C-methylation at high radiochemical purity (>99%) and high specific radioactivity (>130 GBq/μmol). In vitro studies by autoradiography on human brain tissue and in vivo studies by PET in nonhuman primates demonstrated excellent signal-to-noise ratios and a kinetic profile in brain comparable to that of [C]PBB. (S,R)-[C]1 is a promising candidate for measuring changes in endogenous acetylcholine concentrations.

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Discovery of a Novel Muscarinic Receptor PET Radioligand with Rapid Kinetics in the Monkey Brain

Malmquist

Varnäs

Svedberg

et al. 2017

ACS Chem. Neurosci.

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“…3-Quinuclidinyl benzilate (1) M3-(1-azabicyclo[2.2.2]octyl) a-hydroxy-a,a-diphenylacetate, also known as BZ or Ro-2-3308N is an anticholinergic drug of the glycolate series with high psychotoxic potential, about 50-fold that of atropine.1h4 The psychosomimetic properties of 1 possibly are due to accessibility of the lone-pair electrons of the nitrogen. 5 The inability of the bulky side-chain to form intramolecular hydrogen bonds with nitrogen may enhance the availability of the active lone-pair electron. In addition, steric e †ects are important in optimizing interactions between glycolate and receptor.…”

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confidence: 99%