5-HT3 Antagonists Derived from Aminopyridazine-type Muscarinic M1 Agonists

• Published in: Journal of medicinal chemistry Vol. 41; no. 3; pp. 311 - 317
• Main Authors: Rival, Yveline, Hoffmann, Rémy, Didier, Bruno, Rybaltchenko, Volodymyr, Bourguignon, Jean-Jacques, Wermuth, Camille G
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 29.01.1998; Amer Chemical Soc
• Subjects: Animals; Biological and medical sciences; Brain Stem - drug effects; Brain Stem - metabolism; Chemistry, Medicinal; Cholinergic system; Hippocampus - drug effects; Hippocampus - metabolism; In Vitro Techniques; Life Sciences & Biomedicine; Medical sciences; Models, Molecular; Muscarinic Agonists - chemistry; Myocardium - metabolism; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Protein Conformation; Pyridazines - chemistry; Rats; Receptors, Muscarinic - metabolism; Receptors, Serotonin - chemistry; Receptors, Serotonin - drug effects; Receptors, Serotonin, 5-HT3; Science & Technology; Serotonin Antagonists - chemical synthesis; Serotonin Antagonists - pharmacology; CELLS; ACID; CLAMP; RECEPTOR; NO CHOLINERGIC SYNDROME; LIGAND; GRANISETRON; BINDING; SENSORY NEURONS; Rat; Nitrogen heterocycle; Rodentia; Conformational analysis; Central nervous system; Electrophysiology; In vitro; Modeling; Phthalazine derivatives; Vertebrata; Mammalia; Structure activity relation; Hydrochlorides; Animal; Six membered ring; 5-HT3 Serotonine receptor; Molecular model; Bicyclic compound; Pyridazine derivatives; Aromatic compound; Antagonist; Piperazine derivatives; Chemical synthesis; Brain (vertebrata)
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm9705418

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 ([3H] pirenzepine) layed over 10 000 nM. In electrophysiological studies the two most active compounds 10 and13 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.