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Selectivity profile of the novel muscarinic antagonist UH‐AH 37 determined by the use of cloned receptors and isolated tissue preparations
Author(s) -
Wess J.,
Lambrecht G.,
Mutschler E.,
Brann M.R.,
Dörje F.
Publication year - 1991
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1991.tb12161.x
Subject(s) - muscarinic acetylcholine receptor , antagonist , muscarinic antagonist , receptor , chemistry , pharmacology , endocrinology , biology , medicine , biochemistry
1 Functional in vitro experiments were carried out to determine the antimuscarinic potencies of the pirenzepine derivative UH‐AH 37 (6‐chloro‐5,10‐dihydro‐5‐[(1‐methyl‐4‐piperidinyl)acetyl]‐11H‐dibenzo‐[b,e] [1,4] diazepine‐11‐one hydrochloride) at M 1 muscarinic receptors of rabbit vas deferens, M 2 receptors of rat left atria and M 3 receptors of rat ileum. Furthermore, N‐[ 3 H]‐methylscopolamine competition binding experiments were performed to obtain its affinities for the five cloned human muscarinic receptors (m1‐m5) stably expressed in CHO‐K1 cells. Pirenzepine served as a reference drug throughout all experiments. 2 In all preparations used, UH‐AH 37 interacted with muscarinic receptors in a fashion characteristic of a simple competitive antagonist. 3 In the functional studies, UH‐AH 37, like pirenzepine, showed high affinity for M 1 (pA 2 8.49) and low affinity for M 2 muscarinic receptors (pA 2 6.63). In contrast to pirenzepine, UH‐AH 37 also displayed high affinity for M 3 receptors (pA 2 8.04). 4 In agreement with its functional profile, UH‐AH 37 bound with highest affinity to m1 (pK i 8.74) and with lowest affinity to m2 receptors (pK i 7.35). Moreover, it showed a 7 fold higher affinity for m3 (pK i 8.19) than for m2 receptors, whereas pirenzepine bound to both receptors with low affinities. 5 The binding affinity of UH‐AH 37 for m4 and m5 receptors (pK i 8.32 for both receptors) was only ca. 2.5 fold lower than that for m1 receptors, while the corresponding affinity differences were 6 and 13 fold in case of pirenzepine. 6 In conclusion, the receptor selectivity profile of UH‐AH 37 differs clearly from that of its parent compound, pirenzepine, in both functional and radioligand binding studies, the major characteristics being its pronounced M 2 (m2)/M 3 (m3) selectivity. UH‐AH 37 thus represents a useful tool for the further pharmacological characterization of muscarinic receptor subtypes.