New classes of antimuscarinic agents endowed with selective antispasmodic properties. 1-Arylsulfonyl pyrrolidin-2-ones and 2-thiones, 1-arylsulfonyl piperidin-2-ones and 2-thiones and 1-arylsulfonyl hexahydro-2H-azepin-2-one.
A series of 1-arylsulfonylpyrrolidin-2-ones (and 2-thiones), 1-aryl sulfonylpiperidin-2-ones (and 2-thiones) and 1-arylsulfonyl hexahydro-2H-azepin-2-one were synthesized and submitted to a battery of binding assays. The compounds showed little or no affinity for the receptors tested other than muscarinic receptors labelled either with [3H]pirenzepine or with [3H]quinuclidinyl benzilate. When tested in the isolated guinea pig ileum, they antagonized the contractions induced by acetylcholine and behaved as competitive muscarinic antagonists. After parenteral administration in mice, most compounds inhibited carbachol-induced diarrhoea but were less effective in counteracting salivation and lacrimation and showed little or no mydriatic action, thus displaying selectivity at the intestinal level. The reference drugs tested, atropine, butyl scopolamine and cimetropium bromide were far less selective. maximal in vivo activity was obtained by introducing diethylamino or 1-piperidino or 1-hexahydroazepinyl groups in the 4-position of the phenyl ring while the enlargement of a 5- to a 6-membered lactam ring or its conversion into a thiolactam had a less marked effect. The most interesting compounds were further evaluated for their ability to antagonize carbachol-induced colonic hypermotility in the rat and arecoline-induced analgesia in mice. The effect on gastric acid secretion in the rat was also investigated. The overall in vivo data showed that compounds 14, 15, 26 and 27, i.e. those bearing a 1-hexahydroazepinyl group in the 4-position of the phenyl ring, were the most potent and selective compounds.(ABSTRACT TRUNCATED AT 250 WORDS)
Chemistry Department, Roussel Pharma S.p.A., Milan, Italy.
E
E
Toja
C
C
Parini
C
C
Bonetti
P
P
Hunt
M
M
Fortin
F
F
Barzaghi
R
R
Cesana
A
A
Maggioni
A
A
Nencioni
G
G
Galliani
D000818:Animals; D001115:Arecoline / Q000037:antagonists & inhibitors / Q000494:pharmacology; D001285:Atropine / Q000494:pharmacology; D001381:Azepines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D002086:Butylscopolammonium Bromide / Q000494:pharmacology; D002217:Carbachol / Q000037:antagonists & inhibitors / Q000494:pharmacology; D005744:Gastric Acid / Q000378:metabolism; D005769:Gastrointestinal Motility / Q000187:drug effects; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D010276:Parasympatholytics / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011680:Pupil / Q000187:drug effects; D011760:Pyrrolidinones / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism; D012602:Scopolamine Derivatives / Q000494:pharmacology; D013450:Sulfones / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology
D001381:Azepines; D010276:Parasympatholytics; D010880:Piperidines; D011760:Pyrrolidinones; D011976:Receptors, Muscarinic; D012602:Scopolamine Derivatives; D013450:Sulfones; C016859:cimetropium; D002086:Butylscopolammonium Bromide; D001115:Arecoline; D001285:Atropine; D002217:Carbachol