Design and synthesis of sodium (.beta.R*,.gamma.S*)-4-[[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl]thio]-.gamma.-hydroxy-.beta.-methylbenzenebutanoate: a novel, selective, and orally active receptor antagonist of leukotriene D4

Abstract

1573may occur in other drug-receptor systems. For example, opioid phenylmorphans and 3-phenyl-and 4-phenylpiperidines also form such pair^.^^^^"^ A possible molecular explanation for the opposite activity of enantiomers may be the delocalization of charge that occurs when amines are p r o t~n a t e d .~~ That is, rather than being concentrated on the ammonium hydrogen, the positive charge is spread over the adjacent C-N bonds so that the "back" of the N-H bond also contains significant positive charge. Thus, (6aS)-NPA may be able to bind to the same receptor site as (6aR)-NPA since the overall shapes of these molecules are similar and there is sufficient charge at the back of the N-H bond to allow binding to a complementary electrostatic site in the receptor. Antagonists may bind to the same receptor site as agonists, but it appears that agonist activity requires the proper N-H orientation.To summarize, two ((6aS)-NPA and (lS,2R)-5-OH-MDAT) of the three postsynaptic DA antagonists can be closely superimposed with the juxtaposition of the phenyl m-hydroxyl, the N-substituent, and the direction of the N-H bond. The third antagonist, (3S)-PPP, can also assume this conformation with only a moderate energy penalty possibly accounting for its relatively low potency.A similar juxtaposition occurs for the three DA agonists.These observations point out the importance of the orientation of the ammonium hydrogen (or lone-pair electrons) in determining agonist and antagonist activity at DA receptors. This view is consistent with a previous proposal17 that the 6a-hydrogen at the chiral center of aporphines is responsible for the enantiomeric selectivity of such aporphines since the chiral center also determines the orientation of the ammonium hydrogen.Acknowledgment. Dr. Yvonne Martin of Abbott Laboratories provided valuable discussions. This work was supported by the following USPHS grants and awards: RRO5484 (to M.F.) from the National Biomedical Research Program of the NIH, (NINCDS) NS-15439 (to J.L.N.), and (NIMH) MH-47370 and MH-34006 (to R.J.B.). Reamer, M.; Nickander, R. In Problems of Drug Dependence 1981; Harris, L. S., Ed.; NIDA Research Monograph 41: Rockville, MD, 1982; pp 112-118. (46) Awaya, H.; May, E. L.; Aceto, M. D.; Merz, H.; Rogers, M. E.; Harris, L. S. J. Med. Chem. 1984,27, 536-539. (47) Cheng, A.; Uyeno, E.; Polgar, W.; Toll, L.; Lawson, J. A.; De-Graw, J. I.; Loew, G.; Camerman, A.; Camerman, N.

Development of a Three-Dimensional CysLT1 (LTD4) Antagonist Model with an Incorporated Amino Acid Residue from the Receptor

“…Although the chromone residue has not been subjected to extensive SAR studies, in the development of Pranlukast ( 7 ) it was observed that replacement of the chromone by other bicyclic systems devoid of a ketone carbonyl group (e.g., benzodioxans, quinolines, benzofurans, or naphthalenes) resulted in significant decrease of activity . Since several other CysLT 1 antagonists also contain ketone carbonyl groups in this region, − this moiety may be prone to specific interactions with the receptor. We therefore selected this carbonyl (restraint value 2) and the carbon atoms of the acidic moieties (restraint 100) as fitting points.…”

Inhibition of allergen-induced bronchoconstriction in hyperreactive rats as a model for testing 5-lipoxygenase inhibitors and leukotriene D4 receptor antagonists

“…This is best illustrated with the differences between L-649,923 and L-647,438. Both compounds showed similar intrinsic potency in in vitro studies [8,9]. However, the ketobutyric acid sidechain of L-647,438 can undergo facile t-oxidation and the corresponding acetic acid derivative is rapidly eliminated in the rat probably through conjugation.…”

“…Accordingly testing of compounds has been routinely carried out in animals pretreated with methysergide. Two novel orally active 5-1ipoxygenase inhibitors, L-615,919 and L-651,392 [7], and leukotriene D4-receptor antagonists, L-647,438 and L-649,923 [8,9], have been used to illustrate how the model may be used for studying the effects of compounds that modulate the action or production of leukotriene D4. These compounds were tested over a 20 month period using animals from the 13th to 16th generation of this line of rats.…”

The contractile activities of lipoxin A4 and lipoxin B4 for guinea‐pig airway tissues

“…The substances were diluted in 9 glitre-1 saline solution and added to organ baths to establish cumulative dose-response curves within the range of 0.01 nM-l00nM for LTD4 and 1 nM-IO pm for LTB4 and for the lipoxins. In selected experiments, tissues were pre-incubated for 30min at 37°C with defined concentrations of FPL 55712 (7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)2-hydroxypropoxy] -4-oxo-8-propyl-4H-1-benzopyran-2-carboxylic acid, Fisons), L 649923 (sodium(fi5*, yR*) -4 -(3 -(4-acetyly -3 -hydroxy-2 -propylphenoxy) propylthic)-y-hydroxy-,B-methylbenzene-butanoate, Merck Frosst), indomethacin (Sigma) or L 651392 (4 -bromo -2,7 -dimethoxy -3H -phenothiazin -3 -one, Merck Frosst) (Young et al, 1986) a 5-lipoxygenase inhibitor (Guindon et al, 1987), prior to the establishment of cumulative dose-response curves to leukotrienes and lipoxins. In separate experiments, parenchymal tissues were pre-incubated for 30 min at 37°C with a combination of 1O-M indomethacin and 10-5M mepyramine in the presence and absence of 10 -5M L651392.…”