Design, synthesis, and biological evaluation of symmetrically and unsymmetrically substituted methoctramine-related polyamines as muscular nicotinic receptor noncompetitive antagonists

The universal template approach to drug design foresees that a polyamine ca n be modified in such a way to recognize any neurotransmitter receptor. Thu s, hybrids of polymethylene tetraamines and philanthotoxins, exemplified by methoctramine (1) and PhTX-343 (2), respectively, were synthesized to prod uce novel inhibitors of muscular nicotinic acetylcholine receptors. Polyami nes 3-25 were synthesized and their biological profiles were evaluated at f rog rectus abdominis muscle nicotinic receptors and guinea pig left atria ( M-2) and ileum longitudinal muscle (M-3) muscarinic acetylcholine receptors . All of the compounds, like prototypes 1 and 2, were noncompetitive antago nists of nicotinic receptors while being, like 1, competitive antagonists a t,muscarinic M-2 and M-3 receptor subtypes. interestingly, polyamines beari ng a low number of methylenes between the nitrogen atoms, as in 3, 6, and 7 , displayed a biological profile similar to that of 2: a noncompetitive ant agonism at nicotinic receptors in the 7-25 mu M range while not showing any antagonism for muscarinic receptors up to 10 mu M. increasing the number o f methylenes separating these nitrogen atoms in methoctramine related tetra amines resulted in a significant improvement; in potency at nicotinic recep tors. The most potent tetraamine was 19, bearing a 12 methylene spacer betw een the nitrogen atoms, which was 12-fold and 250-fold more potent than pro totypes 1 and 2, respectively. Tetraamines 9-11, bearing a rather rigid spa cer between the nitrogen atoms instead of the very flexible polymethylene c hain, displayed a profile similar to that of 1 at nicotinic receptors, wher eas a significant decrease in potency was observed at muscarinic M-2 recept ors. This finding may have relevance in understanding the mode of interacti on with these receptors. Similarly, the constrained analogue 12 of methoctr amine showed a decrease in potency at nicotinic and muscarinic M-2 receptor s, revealing that the tricyclic system, which incorporates the 2-methoxyben zylamine moiety of 1, does not represent a good pharmacophore for activity at these sites. A most intriguing finding was the observation that the phot olabile tetraamine 22 was more potent than methoctramine at nicotinic recep tors and, what is more important, it inhibited a closed stale of the recept or.