Polymethylene tetraamines: A novel class of cardioselective M₂‐antagonists

In vitro characterization of tripitramine, a polymethylene tetraamine displaying high selectivity and affinity for muscarinic M2 receptors

“…For this reason in the last decade there has been a resurgence of interest in muscarinic receptors owing to the observation that multiple subtypes may exist both in the central nervous system and periphery, which may represent potential targets for therapeutically useful drugs (Hulme et al, 1990;McKinney & Coyle, 1991). Our effort to determine the structural elements of polymethylene tetraamines which confer selectivity toward a muscarinic receptor subtype, rather than to another (Melchiorre et al, 1987b;1989;Melchiorre, 1990) led to the design of tripitramine (Melchiorre et al, 1993). This new tetraamine incorporates ( Figure 1) the structural features of not only methoctramine but also pirenzepine, a selective muscarinic M1 receptor antagonist (Hammer et al, 1980), and of its analogues AF-DX 116 and AQ-RA 741, selective muscarinic M2 receptor antagonists (Eberlein et al, 1992;Hammer et al, 1986).…”

“…Among available muscarinic receptor antagonists, methoctramine, although its discovery dates from only 1987, has contributed significantly to muscarinic receptor subtype characterization and classification owing to its high affinity for muscarinic M2 receptors, low affinity for muscarinic M3 receptors and intermediate affinity for muscarinic Ml receptors (Melchiorre et al, 1987b;1989;Melchiorre, 1988;1990).…”

Interaction between Polyamines and Bacterial Outer Membranes as Investigated with Ion-Selective Electrodes

“…To confirm the importance of these requirements, we examined the effect of methoctramine. This compound, originally developed as an antimuscarinic agent (19), has four amino groups and two methoxyphenyl groups. It was found that methoctramine also induced TPP ϩ uptake at low concentrations, though the concentration range required for Ca 2ϩ release could not be determined owing to the interference from this compound with the Ca 2ϩ electrode.…”

Are m-Cholinoceptors of Guinea Pig Gallbladder Smooth Muscle of m₄ Subtype?

“…They cannot be mj-sites be cause methoctramine had 5.6-to 7.6-fold higher, and 4-DAMP had 10.00-to 19.5-fold lower affinity at these sites than at true m r cholinoceptors [10,12,[23][24][25], Gallbladder m-cholinoceptors cannot be my-subtype be cause of their relatively high affinity for pirenzepine (9.8-to 16.2-fold). HHSiD (6.9-to 7.4-fold) and pf-HHSiD (24.5-to 33.1-fold), and lower affinity for AF-DX 116 (3.2-to 6.0-fold) [7.9, 10, 12,23, 24.…”