Design, synthesis, and biological activity of methoctramine-related tetraamines bearing an 11-acetyl-5,11-dihydro-6H-pyrido[2,3-b][1,4] benzodiazepin-6-one moiety: structural requirements for optimum occupancy of muscarinic receptor subtypes as revealed by symmetrical and unsymmetrical polyamines.
Tetraamines 5-13 and diamines 14-17 as well as monoamine 18 were synthesized, and their biological profiles at muscarinic receptor subtypes were assessed by functional experiments in isolated guinea pig left atrium (M2) and ileum (M3) and by binding assays in rat cortex (M1), heart (M2), and submaxillary gland (M3) homogenates and NG 108-15 cells (M4). An appropriate number and type of substituents on the terminal nitrogens of a tetraamine backbone afforded compounds, such as tripitramine (8) and dipitramine (6), which are endowed with different affinity and selectivity profiles. Tripitramine, a nonsymmetrical tetraamine, resulted in the most potent and the most selective M2 muscarinic receptor antagonist so far available (pA2 = 9.75 +/- 0.02; pKi = 9.54 +/- 0.08). However, it failed to discriminate between M1 and M4 muscarinic receptor subtypes (selectivity ratio: M2/M3, 1600-2200; M2/M1, 81; M2/M4, 41; M1/M3, 28; M4/M3, 55; M4/M1, 2). Dipitramine, another nonsymmetrical tetraamine bearing two substituents on the same terminal nitrogen, displayed the highest affinity for M1 muscarinic receptors (pKi = 8.60 +/- 0.15) and was able to differentiate, unlike 8, all four muscarinic receptor subtypes investigated (selectivity ratio: M1/M2, 5; M1/M3, 2700; M1/M4, 76; M2/M3, 260-520; M2/M4, 15; M4/M3, 35). The results are discussed in terms of a possible mode of interaction of tetraamines with muscarinic receptor subtypes.
Minarini
A
A
Department of Pharmaceutical Sciences, University of Bologna, Italy.
Bolognesi
M L
ML
Budriesi
R
R
Canossa
M
M
Chiarini
A
A
Spampinato
S
S
Melchiorre
C
C
D000818:Animals; D016275:Atrial Function; D001569:Benzodiazepines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism; D015195:Drug Design; D005260:Female; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D008297:Male; D015394:Molecular Structure; D018727:Muscarinic Antagonists; D009119:Muscle Contraction / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism; D011073:Polyamines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D011976:Receptors, Muscarinic / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013363:Submandibular Gland / Q000378:metabolism
D018727:Muscarinic Antagonists; D011073:Polyamines; D011976:Receptors, Muscarinic; C089721:dipitramine; D001569:Benzodiazepines; C084480:tripitramine