1720 Com~n of himbacine and some related compounds on nmscarine M2 and M3 receptors Darroch, S., Taylor *, W., Choo, L.K. and Mitchelson, F. F~wtorianCollegeof Pharmacy, 381 Royal Parade, Melbourne 3052 and * Dept of Chemistry, Universi~ of Sydney, Sydney 2006, Australia A number of alkaloidal compounds related to himbacine, a selec~ve competitive antagonist of muscarine M2 receptors (Gilani and Cobbin, 1986) were studied on the guinea pig isolated left atrium and ileal longitudinal muscle to determine their affinity for M e and M 3 receptor sites respectively these tissues and thus their selectivity. The compounds possessed either a double bond or a saturated link between the two ring systems of the molecule and the N-atom of the piperidine ring was either methylated (himbacine and N-methylhimandravine) or hydrogenated (himbeline and himandravine). None of the compounds exhibited a hig~,er affinity than himbacine for either tissue and saturation of the double bond linking the piperidine ring with the decalin ring system reduced selectivity. Thus the affinity of dihydrohimba- cine for atrial tissue was ca 1-fold less than that of himbacine (-log K n 8.6) and the affinity of both compounds for M 3 receptors was ~milar (--log Ks; 7.5 and 7.4 respectively). The N-methyl group was also important for selectivity when the methyl group in position 2 on the piperidine ring was in the fl, axial position as in himbacine and himbeline but not when the orientation was a, equatorial as in himandravine and N-methylhimandravine. Thus himbeline and its derivative dihydrohimbeline exhibited almost no selectivity but N-methylhimandravine and himandravme exhibited 7- and 8-fold selectivity for M 2 muscarine receptors respectively. The pA 2 values obtained from Schild plots for N-methyihimandravine were 6.2 and 5.3 at M 2 and M 3 receptors respectively and for himandravine the corresponding values were 5.8 and 4.9. The inhibition produced by some of the compounds may not be a simple competitive interaction as the slope of the Schild plot was greater than unity in atrial preparations ,and all of the compounds apart from himbacine and himbeline produced some flattening of the concentration-response curves to carbachol in one or both tissues when used in high concentrations. Refeeence C-ilang S.A.H. and Cobbin LB., 1986, The cardioselectivity of himbacine: a muscarinic receptor antagonist, Naunyn-Schmiedeb. Arch PharmacoL, 332, 16. P.th.0601 The binding properties of se|ective mu.~arinic antagonists in rat brain Ehlert, F.J. and Tran, P. Deparlment of Pharmacology, Collegeof Medicine, Universityof California, Iroine, Irvine, California 92717, U.S.A. The distribution of subtypes of the muscarinic receptor in homogenates of the rat brain was investigated by measuring the competitive inhibition of the binding of [3H]N-methylscopolamine ([3H]NMS) by the Ml-selective m ~ c antagonist pirenzepine and the M2-selective antagonist AF-DX 116 (ll[[2-[(diethylamino)methyl]-I -piperidinyl]acetyl]-5,1 1-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine-6.one). In most brain regions, the pirenzep'-'ne/[3H]NMS and AF-DX ll6/[3H~MS competition curves were consistent with a two-site model. The dissociation constant of pirenzepine for its high affinity site (M~ receptor) was approximately 10 -8 M, whereas the