title: Molecular features necessary for the uptake of diamines and related compounds by the polyamine receptor of rat lung slices.
abstract: The influence of 17 putrescine analogues on the uptake of putrescine and/or paraquat by rat lung slices has been determined. Most of these compounds are competitive inhibitors of putrescine and/or paraquat uptake, but three show no inhibiting activity. Apparent Ki values of the putrescine derivatives increase, and thus the inhibitory effects decrease, with increasing N-methylation. Comparison of N-methyl-1,4-diaminobutane (Ki = 8 microM) with N,N'-bis-methyl-1,4-diaminobutane (Ki = 25.5 microM) shows that a single primary amino group is desirable for high inhibiting activity. Dimethylation at one amino function does not greatly decrease inhibitory potential (thus N,N-dimethyl-1,4-diaminobutane has Ki = 11.5 microM). Increasing the size of N-alkyl substituents in putrescine derivatives, decreased their inhibitory action on the uptake of putrescine. Investigation of the effect of conformationally-restricted analogues of putrescine shows that both (E) and (Z) isomers of 1,4-diaminobut-2-ene are poor inhibitors of putrescine uptake. Analogues of putrescine with bulky substituents on the butyl chain, i.e. the meso- and rac-isomers of 1,1-dichloro-2,3-diaminomethylcyclopropane, do not inhibit putrescine uptake. Inhibiting putrescine derivatives which contain aziridine groups are competitive inhibitors of putrescine and paraquat uptake. Surprisingly, N-(4-aminobutyl)aziridine is the most effective inhibitor of putrescine uptake studied, and is a better inhibitor of paraquat uptake than the endogenous polyamine, putrescine. N-(4-Aminobutyl)aziridine binds reversibly to the polyamine transporter and its inhibitory effects do not appear to be due to any cytotoxic activity of the aziridine. The parameter A (mM)-1 defined as 1000/Ki (where Ki units are microM) was taken as a measure of the affinity of a compound for the polyamine receptor in this paper.
authors.affiliation: Department of Chemistry, The University, Newcastle Upon Tyne, U.K.
authors.forename: M C
authors.initials: MC
authors.lastname: O'Sullivan
authors.forename: B T
authors.initials: BT
authors.lastname: Golding
authors.forename: L L
authors.initials: LL
authors.lastname: Smith
authors.forename: I
authors.initials: I
authors.lastname: Wyatt
mesh_terms: D000345:Affinity Labels / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001388:Aziridines / Q000494:pharmacology; D001665:Binding Sites; D002234:Carbodiimides / Q000494:pharmacology; D003959:Diamines / Q000737:chemistry / Q000493:pharmacokinetics*; D029968:Escherichia coli Proteins; D008168:Lung / Q000033:anatomy & histology / Q000378:metabolism* / Q000648:ultrastructure; D008297:Male; D008968:Molecular Conformation; D015394:Molecular Structure; D010269:Paraquat / Q000737:chemistry / Q000493:pharmacokinetics*; D033902:Periplasmic Binding Proteins; D011700:Putrescine / Q000031:analogs & derivatives / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D011919:Rats, Inbred Strains; D017982:Receptors, Biogenic Amine; D011956:Receptors, Cell Surface / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013997:Time Factors
chemical_list: D000345:Affinity Labels; D001388:Aziridines; D002234:Carbodiimides; D003959:Diamines; D029968:Escherichia coli Proteins; D033902:Periplasmic Binding Proteins; D017982:Receptors, Biogenic Amine; D011956:Receptors, Cell Surface; C049683:potF protein, E coli; C068990:N-(4-aminobutyl)aziridine; D010269:Paraquat; D011700:Putrescine