1988 



Welsh, J. H., and R. Taub. 1950. 



Molecular configuration and biological activity of substances resembling 

 acetylcholine. Science 112(2912): 467-469. 



Using isolated heart of Venus mercenaria as a test object, it was concluded 

 that an ether oxygen and carbonyl group, spatially disposed as in acetyl- 

 choline (ACh) , is of special significance in determining the activity of 

 ACh analogues. The exactness of "fit" or "dovetailing" between all parts 

 of the drug molecule and structures in the receptor molecule are important. 

 ACh may play a role as a coenzyme for an enzyme that regulates membrane 

 polarity and permeability. This further evidence of the significance of 

 molecular configuration in the interaction of ACh analogues and receptor 

 substance is not inconsistent with that hypothesis. - J.L.M. 



1989 



Welsh, John H., and Rae Taub. 1950. 



Structure-activity relationships of acetylcholine and quaternary ammonium 

 ions. J. Pharmacol. Exp. Therap. 99(3): 334-342. 



The test preparation was isolated heart of Venus mercenaria, which has an 

 automatic rhythmicity of beat and an extraordinary sensitivity to acetyl- 

 choline (ACh) . Threshold sensitivity usually is between 10 - 9 and 10~8 m 

 ACh. At 10 to 50 times the threshold dose the heart is stopped in diastole. 

 It was concluded from studies of the actions of quaternary ammonium ions 

 that: 1) at least 2 methyl groups are required for ACh-like activity of such 

 ions on Venus heart; 2) quaternary ammonium ions with 3 or 4 alkyl groups 

 other than methyl have an excitatory action, apparently caused by blocking 

 of residual ACh - these ions also reduce the effect of added ACh; 3) at 

 equimolar concentrations, quaternary ammonium ions with the asymmetry of ACh 

 are more active than symmetrical ions; 4) in the alkyltrimethylammonium 

 series the member with a 5-carbon chain most closely approaches the activity 

 of ACh on Venus heart; and quaternary ammonium ions with 3 or 4 alkyl groups 

 other than methyl (also triethylacetylcholine) have a reversed ACh-like 

 activity on Venus heart and reduce the activity of applied ACh. In the 

 alkyltriethylammonium series, members with an alkyl chain made up of fewer, 

 or more, than 5 carbon atoms had greater blocking activity than amyltriethyl- 

 ammonium ions or triethylacetylcholine. This was not anticipated and is not 

 readily explained. It appears that the shape and size of quaternary ammonium 

 ions, rather than physico-chemical differences such as solubility, determine 

 how closely they approach ACh in their activity. - J.L.M. 



1990 



Welsh, John H., and Rae Taub. 1951. 



The significance of the carbonyl group and ether oxygen in the reaction of 

 acetylcholine with receptor substance. J. Pharmacol. Exp. Ther. 103(1): 

 62-73. 



Many acetylcholine (ACh) analogues have been synthesized and studied 

 pharmacologically, but their relative activities usually have been determined 

 on intact animals or isolated organs rich in cholinesterase. It was thought 

 that an extended series of studies on a single isolated organ with low 

 cholinesterase activity might lead to a better understanding of structure- 

 activity relationships of ACh and at least one type of receptor molecule. 

 Consequently, isolated ventricle of Venus mercenaria was selected as an 

 appropriate test object. Preliminary tests by Welsh and Taub (1948), 

 abstracted elsewhere in this bibliography, showed that Venus heart was indeed 

 a very sensitive indicator of structural changes in the ACh molecule. In the 

 simplest related substances, quaternary ammonium ions, it was found that a 

 minimum of 2 methyl groups was required for ACh-like activity, and other 

 activities were observed for related compounds. Tests were made with 

 quaternary ammonium derivatives of pentanones, 4-ketoamyltrimethyl ammonium 

 ions, quaternary ammonium derivatives of pentanols, substitution of a methyl 

 or acetoxy group for the ketone oxygen of 4-ketoamyltrimethylammonium halide, 

 reversal of position of the carbonyl group and adjacent oxygen and their 

 distance from the quaternary nitrogen, ethoxycholine bromide, and 3-keto- 

 amyltrimethylammonium iodide. Certain substitutions and changes in position 



554 



