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

Abstract

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.

M 3 receptor antagonism by the novel antimuscarinic agent solifenacin in the urinary bladder and salivary gland

“…On the other hand, the organ selectivity of a drug does not necessarily result from receptor selectivity due to a variety of mechanisms (Kenakin 1982). Indeed, an M 3 receptor selective antagonist was shown to be more potent against muscarinic bladder contraction (Kaiser et al 1993). The working hypothesis for solifenacin is based on this latter thoughts.…”

“…However, it often causes the unwanted effect of xerostomia/dry mouth due to antagonism of salivary gland M 3 receptors (Chapple 2000). To address this problem, Kaiser et al (1993) generated an M 3 receptor antagonist selective for the bladder, although the molecular sequences of M 3 receptors are homogenous (Caulfield and Birdsall 1998). Encouraged by their finding, new antimuscarinic agents were screened by functional assays (Naito et al 1998), and solifenacin has been chosen for clinical investigation.…”

Selective blockade of M2 and M3 muscarinic receptors by hexahydrobenzyl‐ fourdapine and a comparison with zamifenacin

“…The values for effects on heart rate in Table 2 range from 7.4 to 5.4, compared with the value 5.4 obtained in vitro, and the values for bloodpressure range from 8.4 to 6.5, compared with 6.6 for ileum in vitro. This might indicate that there are different types of M3 receptors, as has been suggested by Carter et al (1991), Kaiser et al (1993 and Wallis (1995).…”

Synthesis and Bioactivity of Novel Tri-Heterocyclic Molecules: {4-[3-({[5-(Substituted)-1,3,4-Oxadiazol-2-Yl] SulfanyljMethyl) Benzoyl] -1 -Piperazinyl} (2-Furyl)Methanones

“…The piperazine scaffold has been classified as a privileged structure and is frequently found in biologically active compounds across a number of different therapeutic areas [16]. This motif is found in drug candidates displaying anti-depressant, analgesic, antiallergenic, antibacterial, anti-cancer, anti-psychotic, anti-migraine, gastrointestinal agent and cardio tonic agent [17][18][19][20][21][22][23]. Thus, it…”