>> I haven't seen much of Abbott's program lately <<
ooops, just found this..... nifty new product for the tobacco industry.... engineer the smoker..... same product revenues, one tenth the production requirements. Hey, good for the environment too. Might be a tad tough on employment in Virginia for a couple of years......
Eur J Pharmacol 1999 Feb 5;366(2-3):301-8
Gain of function mutation of the alpha7 nicotinic receptor: distinct
pharmacology of the human alpha7V274T variant.
Briggs CA, McKenna DG, Monteggia LM, Touma E, Roch JM, Arneric SP, Gopalakrishnan M, Sullivan JP
Neuroscience Research, Abbott Laboratories, Abbott Park, IL 60064, USA. clark.briggs@abbott.com
In the human alpha7 nicotinic receptor, valine-274 in the pore-lining transmembrane-2 region was mutated to threonine to
produce the variant human alpha7V274T, which was evaluated electrophysiologically following expression in Xenopus laevis
oocytes. Inward current rectification was strong in human alpha7V274T as in the human alpha7 wild type nicotinic receptor.
However, human alpha7V274T was 100-fold more sensitive to the nicotinic receptor agonists acetylcholine, (-)-nicotine and
1,1-dimethyl-4-phenylpiperazinium. Choline also activated human alpha7V274T (EC50 = 12 microM) and was 82-fold more
potent than at human alpha7 wild type nicotinic receptor. (-)-Cotinine, (2,4)-dimethoxybenzylidene anabaseine (GTS-21) and
2-methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine (ABT-089), weak partial agonists at human alpha7 wild type, were much
stronger agonists at human alpha7V274T with EC50 values of 70 microM, 4 microM and 28 microM and fractional activation
values of 93%, 96% and 40%, respectively. However, (-)-lobeline, a human alpha7 wild type nicotinic receptor antagonist, and
dihydro-beta-erythroidine, which activates chick mutagenized alpha7 nicotinic receptors, had only weak agonist-like activity at
human alpha7V274T (< or = 4% of the maximal acetylcholine response). Methyllycaconitine, mecamylamine, d-tubocurarine
and dihydro-beta-erythroidine retained antagonist activity and, indeed, appeared to be at least as potent at human
alpha7V274T as at human alpha7 wild type. These results support and extend the concept that human nicotinic receptor
pharmacology can be profoundly altered by single amino acid changes in the pore-lining segment.
******************
>> was evaluated electrophysiologically following expression in Xenopus laevis oocytes <<
on that note, sad day for biotech and the SIBI/KDUS story......
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