The present article expands on the study of another aspect of structure−activity relationships of the polymethylene tetraamines, namely, the effect of inserting the tetraamine backbone into a macrocyclic structure. To this end, compounds 8−12 were designed by linking the two terminal nitrogen atoms of prototype methoctramine 2 to an aryl moiety. Alternatively, 2 was first modified to achieve compounds 6 and 7, which in turn were cyclized by linking the two terminal primary amine functions to a polyphenyl spacer, affording 13−20. All the compounds were tested on muscle-type nAChRs and most of them as well on AChE. Furthermore, selected compounds were tested also on peripheral M2 and M3 mAChRs. All these cyclic derivatives, like prototypes, were potent noncompetitive antagonists at both frog and Torpedo nAChRs, suggesting that polyamines do not need to be linear or in extended conformation to optimally interact with the nicotinic channel; rather, they may bind in a U-shaped conformation. Relative to muscarinic activity, macrocyclic compounds 10, 13, 14, and 20, in contrast with the profile displayed by 2, were almost devoid of affinity. It is derived that an aryl spacer is detrimental to the interaction of polyamines with mAChRs. Finally, all the diamine diamides investigated in this study were much less potent in inhibiting AChE activity than prototype 3, suggesting that a macrocyclic structure may not be suitable for AChE inhibition.
They have demonstrated that polymethylene tetraamines are a versatile tool for the characterization of different receptor systems.For example, benextramine the prototype tetraamine disulfide for irreversible antagonism of α1-adrenoreceptors, was shown to antagonize several receptors, including nicotinic receptors (nAChRs), muscarinic receptors (mAChRs),2,5 neuropeptide Y receptors, and acetylcholinesterase (AChE). The pharmacological profile of 1 was taken as a starting point to develop the universal template approach to the design of polyamines as selective ligands for different biological targets.4,6,10 Structural modifications performed on the structure of 1 led to the discovery of methoctramine a prototype tetraamine for antagonism of mAChRs, and of caproctamine ,10 a prototype diamine diamide for noncompetitive inhibition of AChE. More recently, they have modified the structure of 2 to produce polyamines that have high affinity and selectivity for muscle-type nAChRs. Following these structural modifications, a most intriguing finding was that the affinity of polyamines for muscle-type nAChRs is dependent on the type and length of the spacer between the nitrogen atoms and on the substituents on the terminal amine functions as well. The higher homologue 4 of 2 was significantly more potent at the frog rectus nAChR than 2, while retaining, however, most of the affinity of 2 for M2 and M3 mAChRs.8 The replacement of the flexible 1,12-diaminododecane unit of 4 with a (4‘ ‘-aminomethyl-[1,1‘;4‘,1‘ ‘]terphenyl-4-yl)methylamine fragment led to 5 (Table 1), which displayed most of the affinity of 4 for nAChRs but lost almost completely the affinity for both M2 and M3 mAChRs. Thus, it was demonstrated that flexibility of the spacer between the inner nitrogen atoms of tetraamines is an important determinant of potency with respect to both nAChRs and mAChRs. Consequently, the selectivity for muscle-type nAChRs relative to mAChRs could be achieved by replacing a flexible spacer with a rigid one. Following this observation, they advanced that the inner nitrogen atoms of 5 are unlikely to be less than 15 Å apart because, owing to the rigidity of the terphenyl moiety, the only possibility to alter the distance between the two inner amine functions is restricted to the rotation along the axis of the two bonds between the inner nitrogen atoms and the 4‘ ‘,4-carbon atoms. It follows that this distance may be important for the interaction with two anionic sites of the channel located most likely at a distance comparable with that between the inner nitrogen atoms of 5.
Design strategy for the synthesis of macrocyclic polyamines of the present investigation. First, methoctramine (2, structure I, R1 = R2 = H, X = CH2) has been modified to achieve structure II by moving the two methoxybenzyl groups from the terminal to the inner nitrogen atoms (a). Second, the outer nitrogen atoms of structures I and II have been linked by a suitable spacer to give structures III (b) and IV (c), respectively.
Chemical structure of benextramine (1, X = S), methoctramine [2, X = (CH2)2], and homologue 4 [X = (CH2)4].
J. Med. Chem. 2002, 45, 15, 3286–3295
Publication Date:June 14, 2002