Guinea pig ileum assay

Methyl-2 -deoxycytidine (437) and 3-methyl-2 -deoxyuridine (438) were isolated from the Swedish sponge Geodia baretti. Compound 437 exhibits strong contractile activity in the isolated guinea pig ileum assay, whereas 438 had no effect on contractions (356). Thymidine-5 -carboxylic acid (439) and 2 -deoxyuridine-5 -carboxylic acid (440), which were previously known only as synthetic products, were found in extracts of the ascidian Aplidium fuscum of the East Pyrenean coast (357). 

Analog (130), having the same substitution pattern as pilocarpine,was equipotent to pilocarpine in a guinea pig ileum assay. In vitro base-catalyzed epimerization of pilocarpine at the C-ethyl group position forms the diaste-reomer isopilocarpine in which pharmacologic activity is lost (171). 

The ester group positional isomer (134) is less potent and less active than arecoline in the guinea pig ileum assay (176), and the N,N-dimethyl quaternary derivative of (134) is slightly more potent than the tertiary amine. 

The five-membered ring congener (135) of arecoline is approximately 50% as muscarini-cally potent as arecoline in a guinea pig ileum assay, and the five-membered ring analog... 

In a series of C-methylated trans-decalin congeners of (229), the 2,3-dimethyl compound (230) was the most potent muscarinic in a guinea pig ileum assay [2% as active as acetylcholine (274)]. 

Figure 15.18. Design and metabolism of soft anticholinergics based on the inactive metabolite-based approach (64, 69 substitutions at two different positions) and the soft analog approach (73). pAg values shown are for in vitro anticholinergic activity determined by guinea pig ileum assay with carbachol as agonist.

The Scandinavian samples possess muscle relaxant activity in the electrically stimulated isolated guinea pig ileum assay (47) and antiviral activity against Herpes and influenza virus (48). Furthermore, the Scandinavian collections contain a mixture of simple monoterpenes with antifouling activity (49). Unfortunately, the muscle relaxing effect, the antifouling activity, and the antiviral activity of the Canadian population have not been reported. 

Neoendorphins, opioid peptides derived from the precursor protein pro-dynorphin (pro-enkephalin B). a-Neoendorphin, H-Tyr-Gly-Gly-Phe-Leu-Arg-Lys-Tyr-Pro-Lys -OH, corresponds to the partial sequence of human and porcine pro-dynorphin-(175-184), and contains the sequence of -neoendorphin ([desLys ]-a-endorphin). Both neoendorphins show potent activity in the guinea pig ileum assay [K. Kangawa et al., Biochem. Biophys. Res. Commun. 1981, 99, 871 N. Minamino et al., Biochem. Biophys. Res. Commun. 1981, 99, 864]. 

The guinea pig ileum assay appears to be able to distinguish three separate lipid soluble toxins obtained from G. toxicus cultures. These toxic fractions isolated from G. toxicus show inhibition of the guinea pig ileum preparations (Miller et al. 1984). 

Figure 3. Design of soft anticholinergics based on the inactive metabolite approach. A few representative soft anticholinergic structures of the methatropine analogue phenylmalonic (3, n = 0, PMTR) and phenylsuccinic series (3. = 1. PSTR). as well as the closely related methscopolamine analogue series (PMSC. PSSC) are also shown together with the antispasmodic p/t2 values determined using in vitro guinea pig ileum assays.

A more recent study on 28 compounds reinforced this observation [77]. It showed that molecular size alone, as measured by calculated effective molecular volume (K) [2] on AMI [33] optimized structures, accounts for -70% of the variance in the pA2 values measured by guinea pig ileum assay (Figure 4) ... 

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