Aims The pharmacodynamic properties of the angiotensin II antagonist candesartan in humans were assessed from the rightward shifts of angiotensin II dose‐effect curves (Schild regression technique). The pharmacokinetic characteristics were determined by radioreceptor assay (r.r.a.) and h.p.l.c. Methods Twelve healthy male volunteers received single oral doses of 4, 8 and 16 mg candesartan cilexetil and placebo. Plasma was obtained for h.p.l.c. and r.r.a. (receptors: rat lung; radioligand: [ 125 I‐Sar 1 Ile 8 ]‐angiotensin II).Before and up to 24 h post dosing angiotensin II was infused in ascending dose steps until blood pressure (systolic and/or diastolic) increased by +25 mmHg. Individual angiotensin II dose‐effect curves were fitted according to an E max model and dose ratios (DR) calculated from the antagonist induced rightward shifts. Results Candesartan, the active metabolite of candesartan cilexetil, declined from peak concentrations at about 4 h with a t 1/2 of about 6 h. A linear relation (slope 1) between h.p.l.c. and r.r.a. data revealed that there is no other active metabolite. DR at 6–9 h post dosing reached a maximum of about 30 and at 24 h still amounted to 4–7, indicating the persistence of a relevant antagonistic effect in vivo . The apparent K i ‐doses (derived from Schild regression plots) indicated a high potency (1.9 mg at 24 h) and slow decline of effect. Between plasma concentrations and antagonistic effect a counterclockwise hysteresis was visible. Conclusions A longer persistence of the antagonistic effect at the receptor site than expected by the presence in plasma indicates a slow off‐rate of candesartan cilexetil from in vivo receptors. This provides an additional rationale for the observed 24 h therapeutic activity of candesartan cilexetil.
Muscarinic acetylcholine receptors (mAChRs) (nomenclature as agreed by the NC-IUPHAR Subcommittee on Muscarinic Acetylcholine Receptors [50]) are activated by the endogenous agonist acetylcholine. All five (M1-M5) mAChRs are ubiquitously expressed in the human body and are therefore attractive targets for many disorders. Functionally, M1, M3, and M5 mAChRs preferentially couple to Gq/11 proteins, whilst M2 and M4 mAChRs predominantly couple to Gi/o proteins. Both agonists and antagonists of mAChRs are clinically approved drugs, including pilocarpine for the treatment of elevated intra-ocular pressure and glaucoma, and atropine for the treatment of bradycardia and poisoning by muscarinic agents such as organophosphates. I
Abstract (R)‐Hexahydro‐difenidol has a higher affinity for M 1 receptors in NB‐OK 1 cells, pancreas M 3 and striatum M 4 receptors (p K i 7.9 to 8.3) than for cardiac M 2 receptors (p K i 7.0). (S)‐Hexahydro‐difenidol, by contrast, is nonselective (p K i 5.8 to 6.1). Our goal in the present study was to evaluate the importance of the hydrophobic phenyl, and cyclohexyl rings of hexahydro‐difenidol for the stereoselectivity and receptor selectivity of hexahydro‐difenidol binding to the four muscarinic receptors. Our results indicated that replacement of the phenyl ring of hexahydro‐difenidol by a cyclohexyl group (→ dicyclidol) and of the cyclohexyl ring by a phenyl moiety (→ difenidol) induced a large (4‐ to 80‐fold) decrease in binding affinity for all muscarinic receptors. Difenidol had a significant preference for M 1 , M 3 , and M 4 over M 2 receptors; dicyclidol, by contrast, had a greater affinity for M 1 and M 4 than for M 2 and M 3 receptors. The binding free energy decrease due to replacement of the phenyl and the cyclohexyl groups of (R)‐hexahydro‐difenidol by, respectively, a cyclohexyl and a phenyl moiety was almost additive in the case of M 4 (striatum) binding sites. In the case of the cardiac M 2 , pancreatic M 3 , or NB‐OK 1 M 1 receptors the respective binding free energies were not completely additive. These results suggest that the four (R)‐hexahydro‐difenidol “binding moieties” (phenyl, cyclohexyl, hydroxy, and protonated amino group) cannot simultaneously form optimal interactions with the M 1 , M 2 , and M 3 muscarinic receptors. When each of the hydrophobic groups is modified, the position of the whole molecule, relative to the four subsites, was changed to allow an optimal overall interaction with the muscarinic receptor.
