title: Actions of the new antimuscarinic compound Lu 25-109 on isolated human and pig detrusor.
abstract: The aim of this study was to evaluate the effects of a novel antimuscarinic agent, Lu 25-109, a partial M1 receptor agonist, and M2/M3 receptor antagonist in human and pig detrusor to establish its affinity for muscarinic receptors in human detrusor and parotid gland and to compare the results with those obtained with oxybutynin. Effects on the detrusor were determined as regards the ability to inhibit carbachol-induced contractions and contractions induced by electrical field stimulation (EFS). Radioligand binding studies were performed to assess the ability to displace quinuclidinyl benzilate (3H-QNB) from muscarinic receptors in the detrusor and parotid gland. Lu 25-109 produced a concentration-dependent rightward shift of the concentration-response curves for carbachol in both human and pig detrusor, the pK(b) values being 6.2+/-0.1 (n=6) and 5.8+/-0.3 (n=6). Corresponding values for oxybutynin were 7.9+/-0.1 (n=7) and 7.8+/-0.1 (n=6). Contractions induced by EFS in human detrusor were almost completely inhibited by 100 micromol/L Lu 25-109 (84+/-4%; n=4). In contrast, EFS-induced contractions in pig detrusor were less sensitive to Lu 25-109, resulting in a final inhibition of 32+/-6% (n=9) with the highest concentration used (100 micromol/L). This difference in effect between human and pig detrusor was not observed with oxybutynin. Radioligand binding experiments demonstrated a small difference in affinity for Lu 25-109 in the parotid gland compared with the bladder, the pKi values being 6.2+/-0.1 versus 6.5+/-0.1 (n=4). Corresponding values for oxybutynin were 8.5+/-0.1 versus 8.2+/-0.1 (n=4). The results show that Lu 25-109 competitively and effectively antagonizes carbachol-induced contractions and contractions induced by EFS in human detrusor muscle. Even if Lu 25-109 were less potent than oxybutynin, it has an effect profile that makes it of interest to test its ability to counteract bladder overactivity in humans.
authors.affiliation: Department of Clinical Pharmacology, Lund University Hospital, Lund, Sweden.
authors.forename: K
authors.initials: K
authors.lastname: Waldeck
authors.forename: B
authors.initials: B
authors.lastname: Larsson
authors.forename: B
authors.initials: B
authors.lastname: Sandberg
authors.forename: K -E
authors.initials: K-
authors.lastname: Andersson
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D018679:Cholinergic Agonists / Q000494:pharmacology; D018680:Cholinergic Antagonists / Q000378:metabolism / Q000494:pharmacology; D004558:Electric Stimulation; D006801:Humans; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000187:drug effects; D008333:Mandelic Acids / Q000378:metabolism / Q000494:pharmacology; D008875:Middle Aged; D018727:Muscarinic Antagonists / Q000378:metabolism / Q000494:pharmacology*; D010306:Parotid Gland / Q000378:metabolism; D011725:Pyridines / Q000378:metabolism / Q000494:pharmacology*; D011813:Quinuclidinyl Benzilate / Q000378:metabolism; D013552:Swine; D013777:Tetrazoles / Q000378:metabolism / Q000494:pharmacology*; D001743:Urinary Bladder / Q000187:drug effects* / Q000502:physiology
chemical_list: D018679:Cholinergic Agonists; D018680:Cholinergic Antagonists; C108369:LU 25-109-T; D008333:Mandelic Acids; D018727:Muscarinic Antagonists; D011725:Pyridines; D013777:Tetrazoles; D011813:Quinuclidinyl Benzilate; D002217:Carbachol; C005419:oxybutynin