Structure-activity relationships of methoctramine-related polyamines as muscular nicotinic receptor noncompetitive antagonists. 2. Role of polymethylene chain lengths separating amine functions and of substituents on the terminal nitrogen atoms.
Polymethylene tetraamine methoctramine (1) is a prototypical antimuscarinic ligand endowed with a significant affinity for muscular nAChRs. Thus, according to the universal template approach, structural modifications were performed on 1 in order to improve affinity and selectivity for the muscle-type nAChR. The polyamine derivatives synthesized were tested at both frog rectus and Torpedo nAChRs and at guinea pig left atria (M(2)) and ileum longitudinal muscle (M(3)) mAChRs. All of the compounds, like prototype 1, were noncompetitive antagonists of nicotinic receptors while being competitive antagonists at M(2) and M(3) mAChRs. The biological profile of polyamines 4-7 revealed that increasing the number of amine functions and the chain length separating these nitrogen atoms led to a significant improvement in potency at nAChRs. Moreover, the role of the number and type of amine functions in the interaction with nAChRs was further investigated through the synthesis of compounds 9 and 10. Tetraamines 8 and 11, bearing a rather rigid spacer between the nitrogen atoms instead of the very flexible polymethylene chain, displayed a profile similar to that of 1 at nAChRs, whereas a significant decrease in potency was observed at mAChRs. Tetraamine 12, bearing a 2-methoxyphenethyl group, was less potent than 1, whereas tetraamine 13, carrying a diphenylethyl moiety, was more potent than 1, confirming that an increase in size of the hydrophobic group on the terminal nitrogen atoms increases significantly the binding affinity for nAChRs. Tetraamines 14-17 were significantly more potent than prototype 2 at both frog rectus and Torpedo nAChRs, confirming that an increase in the distance between the amine functions results in a parallel increase in the affinity for nAChRs. To gain insight into the mode of interaction of polymethylene tetraamines with nAChRs, photolabile (19 and 20) and fluorescent (21 and 22) compounds were synthesized. A most intriguing finding was the observation that 19, which bears two identical azido groups on the terminal nitrogen atoms, was found to bind the Torpedo nAChR with a 1:1 stoichiometry, suggesting a U-shaped conformation in the receptor interaction. Moreover, the high potency shown by fluorescent compounds 21 and 22 appears promising for a further characterization of the polymethylene tetraamines binding site with the muscle-type nAChR.
Rosini
Michela
M
Department of Pharmaceutical Sciences, University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy.
Bixel
M Gabriele
MG
Marucci
Gabriella
G
Budriesi
Roberta
R
Krauss
Michael
M
Bolognesi
Maria L
ML
Minarini
Anna
A
Tumiatti
Vincenzo
V
Hucho
Ferdinand
F
Melchiorre
Carlo
C
D000818:Animals; D016275:Atrial Function; D001593:Benzyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive; D003959:Diamines / Q000737:chemistry*; D004558:Electric Stimulation; D005456:Fluorescent Dyes; D006168:Guinea Pigs; D006325:Heart Atria / Q000378:metabolism; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D008954:Models, Biological; D009119:Muscle Contraction; D009130:Muscle, Smooth / Q000378:metabolism*; D018733:Nicotinic Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010777:Photochemistry; D011073:Polyamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D011898:Ranidae; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000378:metabolism; D012007:Rectum / Q000187:drug effects / Q000502:physiology; D013329:Structure-Activity Relationship; D014101:Torpedo
C453999:7-methoxy-2-oxo-2H-chromene-3-carboxylic acid(3-(6-(8-(6-(2-methoxybenzylamino)hexylamino)octylamino)-hexylamino)propyl)amide tetratrifluorocetate; D001593:Benzyl Compounds; D003959:Diamines; D005456:Fluorescent Dyes; D018733:Nicotinic Antagonists; D011073:Polyamines; D011978:Receptors, Nicotinic; C054938:methoctramine