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The zwitterionic spirocyclic \(\lambda_5\)-germanate bis(2,3-naphthalenediolato( 2-)](pyrrolidiniomethyl)germanate (8) was synthesized and the crystal structure of its tetartoacetonitrile solvate 8 · 1/4 CH\(_3\)CN studied by single-crystal X-ray diffraction. Compound 8 was prepared by reaction of (MeO)\(_3\)GeCH\(_2\)NC\(_4\)H\(_8\) (11; NC\(_4\)H\(_8\) = pyrrolidino) with two equivalents of 2,3-naphthalenediol (isolated as 8 · 1/4 CH\(_3\)CN; yield 92%). The coordination polyhedron around the pentacoordi- naphthalenediolatonate germanium atom of 8 · 1/4 CH\(_3\)CN can be described as a strongly distorted trigonal bipyramid (the structure is displaced by 38.9% from the ideal trigonal bipyrarnid towards the ideal square pyramid), the carbon atom occupying an equatorial position. In the crystal lattice of 8 · 1/4 CH\(_3\)CN, the zwitterions form intermolecular N-H ... o hydrogen bonds leading to the formation of dimers. 1H- and \(^{13}\C-NMR studies revealed that 8 also exists in solution ([D\(_6\)]DMSO).
Starting from trichloro(vinyl)silane (Cl\(_3\)SiCH=CH\(_2\)), the musearinic antagonists sila-biperiden [rac-(SiRS,C2SR>-ao-2] and endosila- biperiden [rac-(SiRS,C2SR)-endo-2] were prepared by a seven-step synthesis. Both silanols are configurationally stableininert organic solvents but undergo slow epimerization in aqueous solution (pH 7.4, 32°C) by inversion of the configuration at the silicon atom. The relative configurations of sila-biperiden and endo-sila-biperiden were detennined by single-crystal X-ray diffraction. Both compounds form intennolecular 0-H · · · N hydrogen bonds in the crystal leading to the fonnation of centrosymmetric dimers (sila-biperiden) and infinite chains (endo-sila-biperiden), respectively. Sila-biperiden is a silicon analogue (C/Si exchange) of the antiparkinsonian drug biperiden [rac-(CRS/C2SR}-exo-1]. In functional phannacological experiments, as well as in radioligand competition studies, biperiden, sila-biperiden and endo-sila-biperiden behaved as simple competitive antagonists at muscarinic Ml-, M2-, M3- and M4-receptors. The three compounds displayed the highest affinity for Ml-receptors (pA\(_2\) values: 8.72-8.80; pK\(_i\) values: 8.8-9.1), intermediate affinity for M4- and M3-receptors, and lowest affinity for M2-receptors (pA\(_2\) values: 7.57-7.79; pK\(_i\) values: 7.7-7.8). The affinity profile (Ml >. M4 > M3 > M2) of biperiden, sila-biperiden and endo-sila-biperiden is qualitatively similar to that of the M1-selective muscarinic antagonist pirenzepine. The antimuscarinic properlies of the C/Si analogues biperiden and sila-biperiden are almost identical.
Starting from chlorodimethyl(phenyl)silane (3), acetyldimethyl(phenyl)silane (l) was prepared by a two-step synthesis in a total yield of 90% [PhMe\(_2\)SiCl (3)-> PhMe\(_2\)SiCCOMe)=CH\(_2\) (4)-> PhMe\(_2\)SiC(O)Me (1)]. The prochiral acetylsilane 1 was transfonned enantioselectively into (R)-(1-hydroxyethyl)dimethyl(phenyl)silane [(R)-2] using plant cell Suspension cultures of Symphytum officinale L. or Ruta graveolens L. Under preparative conditions (300-mg scale, not optimized), (R)-2 was isolated in 15% (Symphytum) and 9% yield (Ruta), respectively. The enantiomeric purities of the products were 81% ee (Syrnphytum) and 60% ee (Ruta), respectively.
The muscarinic receptor mediating vasodilation of resistance vessels in the rat isolated, constant-pressure perfused kidney (preconstriction by w- 7 M cirazoline) was characterized by subtype-preferring agonists and se]ective antagonists. The agonists produced vasodi1ation with the fol1owing rank order of potency: arecaidine propargy] ester (APE) > 5-methylfurtrethonium = methacholine = oxotremorine > (S)-aceclidine > arecaidine 2-butyne-1,4-diyl bisester > 4-Cl-McN-A-343 = (R)-nipecotic acid ethyl ester = N-ethyl-guvacine propargyl ester- (R)-aceclidine = (S)-nipecotic acid ethyl ester > McN-A-343. Agonist-induced vasodilation disappeared after destruction of the endothelium with detergent. Highly significant correlations of agonist potencies for vasodilation were found between rat kidney and guinea-pig ileum submucosal arterioles as weH as agonist potencies at smooth muscle muscarinic M\(_3\) receptors of the guinea-pig ileum. The rank order of antagonist potencies (4-diphenylacetoxy-Nmethylpiperidine methiodide (4-DAMP) > (R)-hexahydro-difenidol - hexahydro-sila-difenidol > pirenzepine - p-fluorohexahydro- sila-difenidol- himbacine- AF-DX 384- AQ-RA 741 > (S)-hexahydro-difenidol) to attenuate vasodilation to APE in rat kidney, correlated significantly with affinities at M\(_3\) receptors in submucosal arterioles and in smooth muscle of the guinea-pig ileum, but differed from those at M\(_1\) and M\(_2\) receptors in rabbit vas deferens. The agonist and antagonist potencies suggest that vasodilation elicited by muscarinic stimuli in endothelium-intact rat renal vasculature is mediated by functional muscarinic M\(_3\) receptors.
Wc invcstigatcd thc binding properlies of thc (R)- and (Sl-cnantiomcrs of thc muscarinic antagonists trihcxyphcnidyl, procyclidinc, hcxahydro-difcnidol. p-fluoro-hcxahydro-difcnidol. hcxbutinol, p-fluoro-hcxbutinnl. and thcir corrcsponding methiodidcs at muscarinic M\(_1\), M\(_2\)• M\(_3\) and M\(_4\) receptor subtypes. In addition. binding properlies of thc (R)- and (S)-cnantiomcrs of oxyphcncycliminc wcrc studicd. The {R)- cnantiomcrs (cutomcrs} of all the compounds had a grcatcr affinity than the (S)-isomcrs for thc four muscarinic rcccptor subtypcs. Thc binding pattcrns of thc (R)- and (S)-enantiomers wcrc gcncrally different. We did not obscrvc any gcncral corrclation hctwccn thc potcncy of thc high-affinity enantiomer and Lhc affinity ratio (cudismic ratio) of the two cnantiomcrs. Thc rcsuhs arc discusscd in tcrms of a 'four suhsitcs' binding modcl.
Bis( 4-fluorophenyl)methyl(l H-1,2,4-triazol-1-yl-methyl)germane (2), a germanium analogue of the agricultural fungicide flusilazole (1), has been synthesized from Cl\(_3\)GeCH\(_2\)CI (3) by both a three-step and a four-step synthesis (3-> (p-F-C\(_6\)H\(_4\))\(_2\)Ge(CH\(_2\)Cl)Br (4)-> (p-F-C\(_6\)H\(_4\))\(_2\)Ge(CH\(_2\)CI)CH\(_3\) (S)-> 2; S ~ (p-F-C\(_6\)H\(_4\))\(_2\)Ge(CH\(_2\)I)CH\(_3\) (6)-> l). The fungicidal properties of l have been compared with those of the parent silicon compound 1 (studies on Si/Ge bioisosterism). In various test systems, the SijGe analogues 1 and 2 showed comparable fungicidal properlies (in activity against plant pathogenic fungi: in agar plate diffusion tests and greenhause evaluations; in activity against human pathogenic fungi: in serial dilution tests). In addition, 1 and 2 displayed comparable potencies in respect of sterol biosynthesis inhibition in Sacclulromycopsis üpolytica and Pyricularia oryzae, the mode of action being primarily an inhtbition of oxidative C14-demethylation.
Muscarinic receptors of rcsistance vessels (submucosal artcrioles, outside diametcr 50-75 J,Lm) from the guinea-pig small intestinc were invcstigatcd in vitro using a computcr-assisted vidcomicroscopy system (Diamtrak <~t ). The muscarinic receptor which mediates vasodilation of prccontractcd [U-46619 (300 nM) or (- )-noradrcnaline (1 0 J.L M)] artcriolcs was characterized with scveral muscarinic agonists and subtypc-sclectivc antagonists. Thc following agonists all produccd cquivalent maximum vasodilation (given in rank ordcr of potency): acctylcholinc = arccaidinc propargyl cstcr (APE) > oxotremorine = ( ± )-muscarinc = ( ± )-mcthacholinc > carbachol > 4-[[N-{4-chlorophenyl)carbamoyl]oxy]-2-hutynyltrimcthylammonium iodide (4-CI-McN-A- 343). 4-([N-(3-ChlorophcnyD-carbamoyl)oxy]-2-butynyltrimcthylammonium chloride (McN-A-343) and N-ethyl-guvacinc propargyl ester (NEN-APE) produccd minimal or no artcriolar vasodilation. Thc muscarinic antagonists pircnzcpinc, ( ± )-5,11-dihydro-11- [[[2-[2-((dipropylamino)methyl}-1-pipcridinyl]ethyl]amino ]-carbonyi]-6H-pyrido(2,3-h)( 1 ,4)-benzodiazcpin-6-onc (AF-DX 384 ), 11- [[ 4-[4-(dicthylamino)butyl]-1-piperidinyl]acetyl]-5, ll-dihydro-6H-pyrido(2.3-h)( 1,4 )-bcnzodiazepin-6-onc (AQ-RA 741 ), p-fluorohexahydro- sila-difcnidol (p-F-HHSiD), 4-diphcnylacetoxy-N-methylpipcridine mcthiodidc (4-DAMP) and (R)- and (S)hexahydro- difcnidol [(R)-HHD, (S)-HHD] shifted thc muscarinc, mcthacholinc or carbachol dosc-rcsponsc curve to the right in a compctitive manner. Schildanalysis of the data yicldcd pA\(_2\) valucs for pircnzcpinc (6.74/6.9), AF-DX 384 (6.72), AQ-RA 741 (6.58), p-F-HHSiD (7.53/7.57), 4-DAMP (9.06), (R)-HHD (7.88/8.32) and (S)-HHD (5.52/5.88). Thus, it can he concluded that submucosal arteriolcs posscss only the M\(_3\) functional muscarinic reccptor, the activation of which causcs hlood vcsscl dilation. The preparation dcscribcd is considcrcd to be a valuable now bioassay for pharmacological investigations of drug actions at muscarinic receptors in the peripheral vascular system.
Four different syntheses of the potent and selective muscanruc antagonist cyclohexyl( 4- fluorophenyl)(3-piperidinopropyl)silanol ( p-fluoro-hexahydro-sila-difenidol, p-F-HHSiD (2b); isolated as hydrochloride 2b· HCl) are described (starting materials: (CH\(_3\)O)\(_2\)SiCH\(_2\)CH\(_2\)CH\(_2\)Cl and Si(OCH\(_3\))\(_4\) ). In addition, the synthesis of the corresponding carbon analogue p-fluoro-hexahydro-difenidol ( p-F-HHD (2a); isolated as 2a· HCI) and the syntheses of three p-F-HHSiD derivatives (3-5), with a modified cyclic amino group, are reported (3: piperidinojpyrrolidino exchange, isolated as 3· HCI; 4: piperidinoj hexamethylenimino exchange, isolated as 4 · HCl; 5: quaternization of 2b with methyl iodide). The chiral compounds 2a, 2b, 3, 4 and 5 were prepared as racemates. In functional pharmacological studies, 3-5 behaved as simple competitive antagonists at musearlnie Ml receptors in rabbit vas deferens, M2 receptors in guinea-pig atria, and M3 receptors in guinea-pig ileal smooth rnuscle. The pyrrolidino (3) and hexamethylenimino (4) analogues of the parent drug p-F-HHSiD (2b) displayed the highest affinity for Ml and M3 receptors (pA\(_2\) values: 7.0-7.4) but exhibited lower affinity for cardiac M2 receptors (pA\(_2\) : 5.9 and 6.0). Their affinity profile (Ml- M3 > M2) is different from that of p-F-HHSiD (2b) (M3 > Ml > M2), but qualitatively very similar tothat of p-F-HHD (2a). The methiodide 5 exhibited the highest affinity for Ml receptors (pA\(_2\) : 8.5) but lower affinity for M2 and M3 receptors by factors of 5.6 and 3.6, respectively.
Racemic dimethylphenyl(l-(phenylacetamido)ethyl)silane [rac-5) has been made by a four-step synthesis starting from (chloromethyl)dimethylphenylsilane [PhMe\(_2\)SiCH2Cl (1) ~ PhMe\(_2\)SiCH(Cl)Me (rac-2) - PhMe\(_2\)SiCH(l)Me (rac-3) - PhMe2SiCH(NH2)Me (rac-4) ~ PhMe\(_2\)SiCH[N(H)C(O)CH\(_2\)Ph]Me ( rac-5); total yield 41% ). Enantioselective enzymatic hydrolysis of rac-5, catalyzed by immobilized penicillin G acylase (E.C. 3.5.1.11) from Escherichia coli 5K (pHM 12), gave (R)-(1- aminoethyl)dimethylphenylsilane [( R )-4] in 40% yield with an enantiomeric purity of 92% ee.