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. 2001 Nov 28;3(4):44–56. doi: 10.1208/ps030430

Receptor binding studies of soft anticholinergic agents

Fenglei Huang 1,✉, Peter Buchwald 1, Clinton E Browne 1, Hassan H Farag 1, Wnei-Mei Wu 1, Fubao Ji 1, Guenther Hochhaus 1, Nicholas Bodor 1,✉
PMCID: PMC2751219  PMID: 12049493

Abstract

Receptor binding studies were performed on 24 soft anticholinergic agents and 5 conventional anticholinergic agents using 4 cloned human muscarinic receptor subtypes. The measured pKi values of the soft anticholinergic agents ranged from 6.5 to 9.5, with the majority being in the range of 7.5 to 8.5. Strong correlation was observed between the pKis determined here and the pA2 values measured earlier in guinea pig ileum contraction assays. The corresponding correlation coefficients (r2) were 0.80, 0.73, 0.81, and 0.78 for pKi(m1), pKi(m2), pKi(m3), and pKi(m4), respectively. Quantitative structure-activity relationship (QSAR) studies were also performed, and good characterization could be obtained for the soft anticholinergics containing at least 1 tropine moiety in their structure. For these compounds, the potency as measured by the pKi values was found to be related to geometric, electronic, and lipophilicity descriptors. A linear regression equation using ovality (Oe), dipole moment (D), and a calculated log octanol-water partition coefficient (QLogP) gave reasonably good descriptions (r=0.88) for the pKi(m3) values.

Keywords: drug design, soft drugs, receptor binding, metabolism, drug evaluation, muscarinic antagonists

Abbreviations

[3H]NMS

N-[3H]-methyl-scopolamine

AQC

(α-cyclopentylphenyl) 3-acetoxyquinuclidium chloride

DMPC

(α-cyclopentylphenyl) methyl-1,2-dimethylpyrrolidinium chloride

MDP

(hydroxymethyl)-3-diisopropylmethylammonium chloride-9-methylxanthene-9-carboxylate

MPC

(α-cyclopentylphenyl) 1-methylpyrrolidinium chloride

PCDT

methoxycarbonylphenylcyclopentylacetoxy-N,N-dimethyl-3-pyrrolidinium methyl sulfate

PCHA.Et

2-phenyl-2-cyclohexen-1-carboxyl-Nα-ethoxycarbonylmethyltropinium methyl sulfate

PCHA.Me

2-phenyl-2-cyclohexen-1-carboxyl-Nα-methoxycarbonylmethyltropinium methyl sulfate

PCHB.Et

2-phenyl-2-cyclohexen-1-carboxyly-Nβ-ethoxycarbonylmethyltropinium bromide

PCHB.Me

2-phenyl-2-cyclohexen-1-carboxyl-Nβ-methoxycarbonylmethyltropinium bromide

PCMS-1

ethoxycarbonylphenylcyclopentylacetyl-N,N-dimethyltropinium methyl sulfate

PCMS-2

methoxycarbonylphenylcyclopentylacetyl-N,N-dimethyltropinium methyl sulfate

PCPA.Et

phenylcyclopentyl-Nα-ethoxycarbonylmethyltropium methyl sulfate

PCPA.Me

phenylcyclopentyl-Nα-methoxycarbonylmethyltropium methyl sulfate

PCPB.Et

phenylcyclopentyl-Nβ-ethoxycarbonylmethyltropinum bromide

PCPB.Me

phenylcyclopentyl-Nβ-methoxycarbonylmethyltropinium bromide

PCTM

methoxycarbonylphenylcyclopentylacetoxy-ethyl-N,N,N-trimethylammonium methyl sulfate

p-F-HHSiD

p-fluoro-hexahydro-sila-difenidol hydrochloride

PMTR

phenylmalonic atropine analogues

PMTR

MeSOMe sulfonyl tropyl 3-phenylmalonate methyl chloride salt

PMTR.TR

di-(8-methyl-8-azabicyclo[3.2.1] oct-3-yl) phenylmalonate dimethiodide

PSTR.TR

di-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl) phenylsuccinate dimethiodide

QSAR

quantitative structure-activity relationship

TMTR.Et

ethyl tropyl 3-thienylmalonate methosulfate salt

TMTR.iPr

isopropyl tropyl 3-thienylmalonate methoiodide salt

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