Pulmonary pharmacology of a novel, smooth muscle-selective muscarinic antagonist in vivo.

The need for a smooth muscle-selective muscarinic antagonist that could provide oral bronchodilator activity with minimal side effects has led to the discovery of 3-(4-benzyl-piperazinyl)-1-cyclobutyl-1-hydroxy-1-phenyl-2-propanone (NPC-14695). Orally administered NPC-14695 was as potent as albuterol in the prevention of aerosolized carbachol-induced collapse in conscious guinea pigs. After s.c. administration in conscious guinea pigs challenged with aerosolized carbachol, NPC-14695 was more potent in the inhibition of collapse than in the inhibition of salivation or the production of mydriasis. Moreover, NPC-14695 exhibited a greater selectivity for the inhibition of collapse over salivary or pupillary effects than either ipratropium or oxybutynin. NPC-14695 was more M3/M2 selective than diphenyl-acetoxy-4-methylpiperidine methiodide (4-DAMP) in vivo, which was determined from the reversal of bronchoconstriction and bradycardia after i.v. administration in anesthetized guinea pigs infused with methacholine, but was less potent than ipratropium or 4-DAMP. At increasing equieffective bronchodilator doses of aerosolized ipratropium and intraduodenally administered NPC-14695 in anesthetized guinea pigs infused with methacholine, ipratropium reversed the bradycardia and then produced tachycardia whereas NPC-14695 did not alter the heart rate. At doses that produced 50% of the maximum bronchodilation, neither aerosolized ipratropium or intraduodenally administered NPC-14695 affected the pupillary diameter or salivation. At doses that produced a maximum bronchodilation, the two drugs produced an equivalent inhibition of salivation and NPC-14695 produced mydriasis. NPC-14695 did not inhibit the bronchoconstriction induced by three other agonists.(ABSTRACT TRUNCATED AT 250 WORDS)

Synthesis and antimuscarinic activity of some 1-cycloalkyl-1-hydroxy-1-phenyl-3-(4-substituted piperazinyl)-2-propanones and related compounds.

A new class of substituted 1-phenyl-3-piperazinyl-2-propanones with antimuscarinic activity is reported. As part of a structure-activity relationship study of this class, various structural modifications, particularly ones involving substitution of position 1 and the terminal piperazine nitrogen, were investigated. The objective of this study was to derive new antimuscarinic agents with potential utility in treating urinary incontinence associated with bladder muscle instability. These compounds were examined for M1, M2, and M3 muscarinic receptor selectivity in isolated tissue assays and for in vivo effects on urinary bladder contraction, mydriasis, and salivation in guinea pigs. Potency and selectivity in these assays were influenced most notably by the nature of the substituent group on the terminal nitrogen of the piperazine moiety. Benzyl substitution was particularly advantageous in producing compounds with functional M3 receptor (smooth muscle) and bladder selectivity; it provided several candidates for clinical study. In vivo, 3-(4-benzyl-piperazinyl)-1-cyclobutyl-1-hydroxy-1-phenyl-2-propanone (24) demonstrated 11- and 37-fold separations in its effect on bladder function versus mydriatic and salivation responses, respectively. The corresponding 2-chlorobenzyl derivative 25 was more than 178-fold selective for M3 versus M1 and M2 muscarinic receptors. 3-(4-Benzylpiperazinyl)-1,1-diphenyl-1-hydroxy-2-propanone (51) was 18-fold selective for M3 versus M1 and 242-fold selective for M3 versus M2 receptors. It was also selective in guinea pigs, where it displayed 20- and 41-fold separations between bladder function and effect on mydriasis and salivation, respectively. In general, the results of this study are consistent with the proposition that the described piperazinylpropanones interact with muscarcinic receptors in a hydrogen-bonded form that presents a conformation similar to that apparently adopted by classical antimuscarinic agents.

Analogues of oxybutynin. Synthesis and antimuscarinic and bladder activity of some substituted 7-amino-1-hydroxy-5-heptyn-2-ones and related compounds.

Oxybutynin chloride [4-(diethylamino)-2-butynyl alpha-cyclohexyl-alpha-hydroxybenzeneacetate hydrochloride, Ditropan] is widely used for the relief of symptoms in neurogenic bladder. This is a result of its combined anticholinergic, antispasmodic, and local anesthetic activities. In a study directed toward development of agents possessing the beneficial properties of oxybutynin, but having a longer duration of action, a series of metabolically more stable keto analogues of the parent ester, i.e. substituted 7-amino-1-hydroxy-5-heptyn-2-ones along with some analogues and derivatives, was prepared and evaluated for in vitro and in vivo antimuscarinic action in guinea pig preparations. Several members of the series were potent antimuscarinics having a longer duration of activity than that of oxybutynin in a guinea pig cystometrogram model. On the basis of its in vitro and in vivo antimuscarinic activity, coupled with a 5-fold greater duration of action than that of oxybutynin, 1-cyclobutyl-7-(dimethylamino)-1-hydroxy-1-phenyl-5-heptyn-2-one (14b) was selected for clinical evaluation.