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Seven coumaric compounds analogous to aurapten were synthesized. Their spasmolytic activity against Ba2+, acetylcholine and histamine was evaluated to investigate their structure-activity relationship. The results of the bioassay demonstrated the important roles of the cis type of double bond at C-2' and the epoxide between c-6' and 7'.

The synthesis of a series of dialkylaminoalkylic esters of 1-chloro-3-carboxy-4-methylisoquinoline and of 1-chloro-3-carboxy-4-phenylisoquinoline is described. The pharmacological activity of some of these compounds was studied. The morpholinoethylester of 1-chloro-3-carboxy-4-methylisoquinoline (VIIa), dimethylaminoethylester (VIIb) and diethylaminoethylester (VIIc) showed a good antispasmodic activity. 4-Phenyl-derivatives (XVa), (XVb), (XVc) were more active than analogous 4-methyl derivatives; particularly the diethylaminoethylester of 1-chloro-3-carboxy-4-phenylisoquinoline (XVc) showed an antagonist effect against spasmogens similar to that of papaverine.

This paper reports the synthesis of 2- and 4- [benzyl-(2-dimethylaminoethyl)amino]pyrimidine compounds and the evaluation of their inhibitory properties against histamine (H1), acetylcholine and barium chloride, on guinea pig isolated ileum. 4-[p.Methoxybenzyl-(2-dimethylaminoethyl)amino]-2-methoxy-pyrimidine (VIII) is shown to possess H1 receptor antagonist activity, with a potency similar to that observed for Tonzylamine. By contrast, a specific, although weak, antimuscarinic effect is displayed by 4-[benzyl-(2-dimethylaminoethyl)amino]-2-methoxy-5-methylthio-pyrimidine (XII).

Dicyclomine inhibition of acetylcholine-induced and barium chloride-induced isotonic contractions of the smooth muscle from three segments of the lower urinary tract (bladder body, bladder base, and proximal urethra) of the guinea pig and the rabbit was studied in vitro. In the guinea pig dicyclomine caused competitive inhibition of acetylcholine-induced contraction of the bladder body (1 x 10(-7) M to 1 x 10(-5) M) and the bladder base (1 x 10(-6) M, 1 X 10(-5) M) and was less potent than atropine and propantheline. In the rabbit significant blockade of acetylcholine-induced contractions occurred at dicyclomine concentrations of 5 x 10(-6) M to 3 x 10(-5) M in the bladder body and at 1 x 10(-5) M and 3 x 10(-5) M in the bladder base. In both species dicyclomine inhibitory effects were most marked in the bladder body, moderate in the bladder base, and minimal in the proximal urethra. Dicyclomine failed to cause inhibition of the barium chloride-induced contractions in the guinea pig vesicourethral smooth muscle. In rabbits, however, significant antagonism P less than 0.01) of barium chloride-induced muscle contraction was observed with dicyclomine at concentration 1 x 10(-5) M in both bladder body and the bladder base. The clinical implication of such properties of dicyclomine are discussed.

A number of amines derived from 1,3-bis(3,4-methylen-dioxyphenoxy)propane have been prepared from 1,3-bis-(3,4-methylendioxy-phenoxy)propan-2-one. The acute toxicity and the activity of these compounds on isolated guinea pig ileum have been studied. The majority of the compounds showed clear antagonist activity towards BaCl2, histamine and acetylcholine contracting responses, generally grater than that of papaverine; on the contrary, their antagonist activity towards 5-HT responses was slightly lower.

Experiments have been conducted which show that while the tertiary amine oxybutynin has only moderate in vitro anticholinergic and antihistaminic activity, it is a potent inhibitor of barium chloride-induced spasms of rabbit detrusor muscle. Oxybutynin exerts 1/13 the anticholinergic activity of propantheline and 1/4 that of atropine, but produces approximately 2x the inhibition of barium chloride-induced spasm than propantheline and 10x the inhibition produced by atropine. In sum, oxybutynin possesses a notable antispasmodic activity distinct from its anticholinergic activity and stronger than that of atropine, propantheline, or methantheline, which may prove useful in the treatment of smooth muscle hypermotility.

Oxybutynin chloride exerts a moderate anticholinergic effect on rabbit detrusor in vitro, which is reversible and competitive in nature (KB = 4.7 x 10(-9), and midway in potency between atropine and papaverine. In addition, oxybutynin strongly antagonizes BaCl2-induced spasms of detrusor with a potency equivalent to that of papaverine and 10 times that of atropine. This musculotropic spasmolytic effect is slightly greater in rabbit than human or monkey tissue, and noncompetitive (pD2 = 5.5). This direct relaxant effect, unlike that of papaverine, is not mediated by the inhibition of tissue phosphodiesterase, but probably reflects oxybutynin's local anesthetic properties and associated effects on Ca++ fluxes and binding.

The interaction of papaverine and tiemonium alone or combined, with BaCL2 and histamine on guinea pig ileum and with acetylcholine on rat jejunum have been studied with the help of molecular pharmacology techniques. The competitive antagonist effects of tiemonium and the non competitive antagonist effects of papaverine are evidenced and shown to be strictly additive when the two drugs are combined. This reflects a sequential blockage of the effects of acetylcholine, histamine and barium ions at the smooth muscle level. No such antagonism has been previously described in the case of the interaction with barium chloride with any other combination of two spasmolytic drugs.

Butylidenephthalide (BdPh), ligustilide and butylphthalide were isolated and purified from neutral oil of Ligusticum wallichii Franch. Among these three, BdPh proved to be the most active in inhibiting rat uterine contractions induced by prostaglandin F2 alpha, oxytocin and ACh. In studies done to compare the effects of BdPh and papaverine (Pap), guinea pig ileum, vas deferens and taenia coli were used. BdPh inhibited contractile responses of the ileum to agonists including ACh, K+ and Ba2+ in normal Tyrode solution and to exogenous Ca2+ in high K+ (80 mM), Ca2+-free Tyrode solution, and also responses of vas deferens responses to norepinephrine. Thus, BdPh is a non-specific antispasmodic but weaker in potency than Pap. However, as the inhibitory effects of BdPh on phasic contraction (PC) and tonic contraction (TC) of preparations, including depolarized and non-depolarized ileum and taenia coli, were much the same, it is suggested that the action mechanism of BdPh may differ from that of Pap which inhibited TC more selectively than PC. It may be concluded that BdPh possesses an non-specific antispasmodic action like Pap, the mechanism of action being different from that of Pap.