P Selective antagonist

Rinaldi-Carmona M, Bath F, Heaulme M, Shire D, Calandra B, Congy C, Martinez S, Maruani J, Neliat G, Caput D, Ferrara P, Soubrie P, Breliere JC, Lefur G. SR14176A, a potent and selective antagonist of the brain cannabinoid receptor. FEBS Lett 1994 350 240-244. 

Fig. 4.5 Central receptor occupancy after oral administration of p-adrenoceptor antagonists A, atenolol B, metoprolol C, pindolol D, propranolol. The high occupancy of pi receptors does not correlate with physicochemical properties (lipophilicity). The occupation of p2 receptors correlates with sleep disturbances and the intrinsic selectivity of the compounds.

ETA-selective antagonists included a more selective (>25 000-fold) p)rrrolidine carboxylic acid derivatives A-216546 (121). A-216546 was orally available in rat, dog and monkey and blocked endothelin-1-induced presser response in conscious rats. Replacement of the dialkylacetamide side chain in 121 resulted in a complete reversal of receptor selectivity, preferring ETb over ET. Compound 122 (A-308165) demonstrated over 27 000-fold selectivity favouring the ETb receptor. So far one of the endothelin ETA-receptor antagonists bosentan (123) has reached the market for the treatment of pulmonary h)rpertension. Several other compounds have either failed in the clinic or are in various stages of development (e.g. sitaxsentan (124) and 125). ... 

Because the p-receptors of the heart are primarily of the pi type and those in the pulmonary and vascular smooth muscle are p2 receptors, Pi-selective antagonists are frequently referred to as cardioselective blockers. The intrinsic activity, cardioselectivity, and membrane-stabilizing actions of a number of p-blockers are summarized in Table 11.2... 

A. Both sets of responses to isoproterenol are mediated by p-adrenoceptors, and all the choices are p-antagonists. However, drug X is more effective in antagonizing cardiac responses to isoproterenol than it is the bronchiolar responses. Drug X is therefore a cardioselective p-blocker, that is, selective for Pi over P2 receptors. Metoprolol is the only pi-selective antagonist among the choices. 

Recently, the 2-[ F]fluoroethylation of a phenolic desalkyl precursor based on the jSi-AR-selective antagonist ICI 89,406 was realized via a two-step synthesis starting with the [ F]fluorination of ethylene glycol di-p-tosylate. The radiosynthesis yielded (S)-A/-[2-[3-(2-cyano-phenoxy)-2-hydroxy-propylamino]-ethyl]-A/ -[4-(2-[ F]fluoroethoxy)-phenyl]-urea 10, representing a potent F-labeled high affinity / i-AR-selective radioligand with a / i-AR-selectivity of >40.000 (Fig. 15) [107],... 

B.W. Griffin, P. Klimko, J.Y. Crider, N.A. Sharif, AL-8810 A novel prostaglandin F2 alpha analog with selective antagonist effects at the prostaglandin F2 alpha (FP) receptor, J. Phamacol. Exp. Then 290 (1999) 1278. 

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