In the first part of this study, devoted to the discovery of selective antimuscarinic agents, (+/-)- N-[5-[(1'-phenyl-1'-cyclohexylacetoxy)methyl]-2-furfuryl]dimeth yla mine (5a) proved to be at least 20 times more potent in the rat ileum and bladder than in guinea pig atria. Several (+/-)-N- [5-[(1'-substituted-acetoxy)methyl]-2-furfuryl]dialkylamine analogs of 5a were subsequently prepared. This involved exploration of the tertiary nitrogen substituents and modulation of the lipophilic side chain at position 5 of the furan ring, using the Hansch approach. A QSAR study was conducted to correlate activity with physicochemical properties of substituents. The possibility of describing all compounds in a single model indicates that variations of nitrogen and the lipophilic side chain contribute independently to activity. Compounds 5b, c,j, with bulky lipophilic substituents at the tertiary nitrogen, showed unprecedented selectivity between the two smooth muscle tissues, their antimuscarinic potency being from 10 to 90 times higher in the ileum than in the bladder. It is suggested that their interesting tissue selectivity is probably related to nonspecific phenomena involving the receptor environment, rather than real differences between the muscarinic receptors in the two tissues.

An isolated preparation of the guinea-pig trachea is described which allows the simultaneous measurement of acetylcholine release and smooth muscle contraction. Incubation of the epithelium-free preparation with [3H]choline resulted in the formation of [3H]acetylcholine. Electrical stimulation caused the release of [3H]acetylcholine and a contractile response. Tetrodotoxin and omission of calcium from the medium abolished both the evoked release and contractions. The muscarinic agonists oxotremorine, carbachol and pilocarpine concentration-dependently inhibited the electrically evoked acetylcholine release and contracted the tracheal smooth muscle. Pre- and postsynaptic EC50 values for a given agonist were not different. Atropine (100 nmol/l) significantly facilitated the evoked acetylcholine release. A concentration of 10 nmol/l atropine did not change the evoked release but antagonized the inhibitory effect of oxotremorine. It is concluded that presynaptic muscarine autoreceptors inhibit the release of acetylcholine from parasympathetic nerves of the guinea-pig trachea.

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1. The present study was carried out to look at the effect of different calcium antagonists on the response to noradrenaline in the whole and bisected rat vas deferens considering that the response consisted of three components (I) the phasic response (II) the tonic response and (III) the spikes (rhythmic contractions). 2. Nifedipine (3 x 10(-9)-1 x 10(-7) M) inhibited all the components at the same concentration range, verapamil (1 x 10(-7)-1 x 10(-5) M) inhibited the phasic and tonic response but not the rhythmic activity. This latter component, at a certain concentration range and especially in the prostatic portion was markedly potentiated. Diltiazem and flunarizine lay in an intermediate position. 3. Papaverine, a Ca2+ antagonist that acts mainly intracellularly, inhibited preferentially the tonic component; ryanodine was practically inactive. 4. Cromakalim inhibited only partially the phasic and tonic components but totally inhibited the rhythmic contractions. 5. These results can be explained by postulating two types of calcium channels opened by alpha-adrenoceptor stimulation. The first one is verapamil- and nifedipine-sensitive and allows the entry of Ca2+ directly available for the contraction and responsible for the phasic and partially responsible for the tonic component. The second channel is merely nifedipine-sensitive and allows the entry of Ca2+ trigger which can release Ca2+ from intracellular sites: the mobilized Ca2+ is able to sustain the tonic component and is the main one responsible for the rhythmic activity. There is the possibility that this second channel is associated with ATP-sensitive K+ channels.