5-HT₃ antagonists derived from aminopyridazine-type muscarinic M1 agonists

A conformational analysis, performed on muscarinic M₁ agonists, identified four structural features characteristic of the muscarinic M₁ pharmacophore: (i) a protonable basic or quaternary nitrogen acting as a cationic head; (ii) an electronegative dipole usually part of a planar mesomeric ester, amide, or amidine function which can be replaced by an ether (muscarine) or a dioxolane (AF 30); (iii) an intercharge distance of 5 ± 0.5 Å between the cationic head and the electronegative atom of the dipole; (iv) an elevation of 0.5 ± 0.03 Å of the cationic head over the plane containing the electronegative dipole. During a reinvestigation of the conformational behavior of published structures of 5-HT₃ antagonists, similar features were observed for the 5-HT₃ pharmacophore. However many 5-HT₃ antagonists possess additional aromatic planes not present in the muscarinic M₁ agonists. These observations brought us to predict the chemical modifications that would change muscarinic M₁ agonists into 5-HT₃ antagonists. Four of the predicted aminopyridazines were actually synthesized and submitted to testing. The observed IC₅₀ values for 5-HT₃ receptor binding ([³H] BRL 43694) ranged from 10 to 425 nM, whereas the affinities for the muscarinic receptor preparations ([²SH] pirenzepine) layed over 10 000 nM. In electrophysiological studies the two most active compounds 10 and 13 produced antagonist-like effects on the 5-HT receptor channel complexes responsible for the generation of the rapidly desensitizing ionic currents, and agonist- like effects on those responsible for the slowly desensitizing components.