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Some new oxime ethers of types 7 and 8, in which the methyleneaminoxy group, C=N-O, of oxiconazole 6 is in an inverted atomic sequence, were synthesized and tested for their antifungal activities. Among them, the type 7 compounds, such as the N-ethoxy-morpholino-substituted derivatives 7l-o (Table 1), showed good antifungal properties against the Candida strains tested, with minimum inhibitory concentration (MIC) values similar to those of the reference drug 6. A remarkable result was obtained with these types of azoles, which had shown a cidal character against Candida albicans, while the reference drug oxiconazole was only fungistatic in the same tests. This fact may be seen from a comparison of the MIC values with those of the minimum fungicidal concentration (MFC) values for most of the type 7 compounds assayed that have shown differences between the MIC and the MFC, which are lower than three double diluitions. A simple molecular modeling of the P450 14-alpha-sterol demethylase from C. albicans (Candida P450DM) was built in order to understand how the structural differences between type 7 compounds and oxiconazole 6 can induce different antifungal profiles. The results of this work seem to confirm that it is possible to reverse the atomic sequence of the methyleneaminoxy group, C=N-O, of 6, obtaining new imidazoles possessing good antifungal properties.

The (E)-[2-(4-Methylsulphonylphenyl)-1-cyclopentenyl-1-methyliden](methyloxy)amine (5) and (arylmethyloxy)amines (6–12) were designed in order to verify the effects on the biological properties of the substitution of an aryl of selective diarylcyclopentenyl cyclooxygenase-2 (COX-2) inhibitors of type 3 with a methyleneaminoxymethyl moiety (MAOMM). Compounds 5–12 were tested in vitro for their inhibitory activity towards COX-1 and COX-2 by measuring prostaglandin E2 (PGE2) production in U937 cell lines and activated J774.2 macrophages, respectively. The compound with the highest in vitro activity towards COX-2 (9) was also assayed in vivo for its antiinflammatory activity by means of the carrageenan-induced paw edema test in rats. Some of the new compounds showed an appreciable in vitro COX-2 inhibitory activity, with IC50 values in the μM (6,7,9,10,11) range. Compound 9 also exhibited an appreciable in vivo activity (29% inhibition at a dose of 30 mg kg−1) when administered intraperitoneally. The structural parameters of 9 were determined by X-ray crystallographic analysis.

3-Phenylpiperidines (PPEs) have been thoroughly investigated in view of their interesting dopaminergic activity, and the N-n-propyl substitution has been suggested as the most effective among several PPEs differently substituted on the phenyl ring. In previous studies, we found that the dimethyl substitution on the phenyl ring of N-unsubstituted PPEs provided compounds active toward alpha2-adrenergic receptors (alpha2-ARs), which proved to possess interesting selectivity properties. The high degree of homology between the binding domains of alpha2-ARs and D4-dopaminergic receptors (D4-DARs) prompted us to verify whether this kind of substitution on the aromatic ring might prove to be active against retinal DARs of the D4 subtype. On the basis of these premises, we synthesized the dimethylphenyl-substituted PPEs 4a-f, in which an n-propyl chain is present on the aminic nitrogen. Radioligand binding assays on bovine retina and striatum membranes for D1-like and D2-like DARs indicated that PPEs 4a, 4b, and 4f possess a high affinity and selectivity for the D4-DAR subtype of bovine retina.

Summary Previous drug—receptor interaction mechanism studies at the molecular level of adrenergic drugs made it possible to construct two three-dimensional molecular models, A and B, using conformationally restrained cyclic analogues of natural catecholamines, including 3-(3,4-dihydroxyphenyl)-3-piperidinol (3-DPP, 3); these models offer useful information about the steric requirements for the direct activation of α1- and α2-adrenergic receptors, respectively. In order to gain further knowledge about the steric requirements of these receptors, we also synthesized 3-(3,4-dihydroxyphenyl)-c-2-methyl-r-3-piperidinol (2-MDPP, 8) and the 3-(3,4-dihydroxyphenyl)-c- and -t-6-methyl-r-3-piperidinols (6-MDPPs 9 and 10); these differ from the 3-DPP 3 used for the construction of the molecular models exclusively in the presence of a methyl in the 2 or 6 position of the heterocyclic ring. The configuration and conformation of the MDPPs 8–10 were assigned by 1H-NMR and IR studies, and confirmed by conformational analysis performed by means of theoretical calculations. The α1- and α2-adrenergic properties were evaluated in vitro both by radioligand binding assays and by functional tests on isolated preparations. The results obtained made it possible to obtain a more refined steric definition of the A and B models.

Summary The chiral (S)- and (R)-N-[3-(isopropylamino)-2-hydroxypropylidene](p-chlorophenylmethyloxy)amines ((S)-1a and (R)-1a) and their corresponding N-tert-butyl-substituted analogs ((S)-1b and (R)-1b) were synthesized from optically active precursors of known absolute configuration by procedures which had no effect on the configuration of the asymmetric carbon. Compounds (S)-1a,b and (R)-1a,b were tested for their β-adrenergic properties by radioligand binding experiments and functional tests on isolated preparations. The biopharmacological results show that compounds (S)-1a,b, in which the geometry of the chiral carbon adjacent to the hydroxyl group resembles that of natural catecholamines with the R configuration, interacted better with β-receptors, even if the stereochemical selectivity among enantiomeric pairs is not particularly marked.

The tetrahydronaphthalene analogs 4 and 5 of DCI ( 3b ) and of its N -unsubstituted derivative ( 3a ) were synthesized and tested for their β-adrenergic properties by means of both binding tests and functional tests. Compounds 4 and 5 proved to possess a good affinity for β-adrenergic receptors accompanied by an appreciable β-blocking activity, thus indicating that the formal insertion of a β-blocking drug such as DCI into a tetrahydronaphthalene structure is able to provide compounds which still possess a β-blocking activity.

Summary The chiral (S)- and (R)-N-[3-(isopropylamino)-2-hydroxypropylidene](p-chlorophenylmethyloxy)amines ((S)-1a and (R)-1a) and their corresponding N-tert-butyl-substituted analogs ((S)-1b and (R)-1b) were synthesized from optically active precursors of known absolute configuration by procedures which had no effect on the configuration of the asymmetric carbon. Compounds (S)-1a,b and (R)-1a,b were tested for their β-adrenergic properties by radioligand binding experiments and functional tests on isolated preparations. The biopharmacological results show that compounds (S)-1a,b, in which the geometry of the chiral carbon adjacent to the hydroxyl group resembles that of natural catecholamines with the R configuration, interacted better with β-receptors, even if the stereochemical selectivity among enantiomeric pairs is not particularly marked.

The diastereoisomeric N -isopropyl- and N-t -butyl-substituted 2-(5′-(3′-phenyl)- and 2-(5′-(3′-isopropyl)isoxazolidinyl)-ethanolamines ( 5–8 ), which can be viewed as conformationally restrained analogs of the corresponding β-blocking oxime ethers 10 and 11 , were synthesized. The relative configurations of 5–8 were assigned by 1 H-NMR studies and by the determination of the solid-state structure of one of the new compounds ( 6a ). The new isoxazoline derivatives ( 5–8 ) were tested both by radioligand binding assays and by functional tests on isolated preparations. Compounds 5a–8a were found to retain, albeit to a lower extent, the β-blocking properties of the corresponding oxime ethers 10a and 11a , thus indicating that these last compounds may prove to be still capable of interacting with the β-receptors, even if their C = NOCH 2 portion is constrained in a conformationally semi-rigid isoxazoline structure. Possible rationalizations of the results were sought by comparing the conformations and the molecular reactivity of model compounds of the isoxazolines 5–8 and of the oxime ethers 10 and 11 .

The alpha 1-, alpha 2-, beta 1-, and beta 2-adrenergic properties of the 2-(3,4-dihydroxyphenyl)morpholines 3 and 4 (2-DPMs), of the 3-(3,4-dihydroxyphenyl)-3-piperidinols 5 and 6 (3-DPPs), and of the trans-2-amino-5,6-dihydroxytetrahydronaphthalen-1-ols 7 and 8 and the trans-2-amino-6,7-dihydroxytetrahydronaphthalen-1-ols 9 and 10 (2-ADTNs) were evaluated in vitro both by radioligand binding assays and by functional tests on isolated preparations and compared with those of norepinephrine (NE, 1) and isoprenaline (ISO, 2). Through a comparison of the stereostructures of the compounds examined with their biopharmacological properties, it was possible to revise previously proposed molecular models for the direct activation of alpha- and beta-adrenergic receptors. The revised models (A-C) provided information about the conformational requirements of adrenergic drugs, which substantially fit in with the results of several published studies involving conformationally-restricted adrenoceptor agonists. The different position of the catecholic hydroxyl groups in model B, which refers to the alpha 2 receptors, and in model C, which refers to the beta receptors, confirms the importance of the rotameric position of the aromatic ring of catecholamines in the interaction with the alpha- and beta-adrenergic receptor.

The molecular parameters of the tetrabutylammonium salt 3 of the monobactam antibiotic 2 were determined by means of X-ray cyrstallographic analysis. Crystals are monoclinic, space group P21 with Z = 4, unit-cell dimensions a = 17.368(3), b = 19.101(4), c = 9.464(2) A , β = 94.25(1)° . In the asymmetric unit of 3 2 independent molecules (3a and b) are present. The structure was solved by direct methods and refined by a least-squares procedure to an R value of 0.049 for 4 346 unique observed reflections. The relevant molecular parameters of 3 compare well with the corresponding ones of sulfazecin 1, the only biologically active monobactam antibiotic subjected to crystal-structure determination.

The 3-aminoxy-( E )-2-methoxyiminopropionyl penicillins 13 and cephalosporins 14 and 15 were synthesized and assayed for their antimicrobial activity on Gram-positive and Gram-negative bacteria whether producers of β-lactamases or otherwise. Compounds 13 , 14 , and 15 exhibited an activity which was generally lower than that of the corresponding phenylacetyl derivative: penicillin G ( 4 ), cephaloram ( 5 ), and phenylacetamidodesacetoxycephalosporanic acid ( 6 ). Furthermore, the comparison of the minimum inhibitory concentration values of some of the new 2-methoxyimino 3-aminoxypropionyl derivatives 13–15 with those of the corresponding ones 1–3 lacking the 2-methoxyimino substituent showed that the introduction of the 2-methoxyimino group of E configuration on the aminoxypropionamido side chain of 1–3 gives compounds ( 13–15 ) which do not generally possess better antimicrobial properties.

We have previously reported that compounds dimethyl-substituted on the phenyl ring of N-n-propyl-3-phenylpiperidines (PPEs) have a high (nM) affinity and selectivity toward the D(4) dopamine receptor (D(4) DAR) with m,p-dimethyl PPE (1) having the highest affinity and selectivity. In the present paper we have investigated the role of the methyl substitution by the synthesis of monomethylated (2a-c) and nonmethylated (2d) PPEs followed by the characterization of their biological properties using receptor binding assays. Our findings reveal that the methyl substitution of the phenyl ring is not necessary for a high and selective binding affinity to the D(4) DAR. Moreover, we have also synthesized cyclohexylpiperidines (CHPEs, 3a-d), which all showed higher binding affinities for the D(4) DAR than their aromatic counterparts. These results indicate that a pi-pi type interaction of the phenyl ring of PPEs with the D(4) DAR might not be essential, whereas a simple hydrophobic attraction between the cyclohexyl substituent of CHPEs and a hypothesized lipophilic pocket of the receptor might be crucial. Furthermore, functional assays indicate that 3d, as well as 1, are partial agonist at the D(4) DAR and therefore might represent new pharmacological tools to investigate the role of D(4) DAR activation in the control of cognitive functions and emotional states in health and disease.

The 5,6- (5a) and 6,7-dihydroxy-3,4-dihydrospiro[naphthalen-1 (2H)-3′-piperidine] (6a) and their N-isopropyl derivatives (5b and 6b), DDSNPs, were synthesized. These compounds can be viewed as the result of the combination of the structure of the 3-(3,4-dihydroxyphenyl)-piperidine 2a or 2b, with the structure of the corresponding 1-(aminomethyl)-5,6-dihydroxy-(3a or 3b) or 1-(aminomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (4a or 4b), 1-AMDTNs. The new compounds (5a, b and 6a, b) were assayed for their α and β adrenergic properties by means of binding experiments and functional tests and the results were compared with those obtained for catecholamines 1a, b and the previously described 3-(3,4-dihydroxyphenyl)piperidine (3-DPP; 2) and 1-AMDTNs (3, 4). Comparison of the affinity and activity data of novel derivatives with those of reference compounds 2, 3 and 4 shows a general low ability of DDSNPs 5 and 6 to interact with both α and β- adrenoceptors.

Some monocyclic β-lactam derivatives of type 3 (MAOAs) in which the leaving group (LG) on the C(4) is a methyleneaminoxy moiety, were synthesised and tested in vitro and in vivo for their inhibitory activity towards human leukocyte elastase (HLE). Some compounds showed an appreciable in vitro inhibitory activity against this enzyme. Effects on the anti-HLE activity due to the nature of the substituents R and R1 present on their LG were observed and rationalised by means of molecular modelling techniques. The results of in vivo pharmacological tests indicated that MAOAs, while showing an inhibitory activity on the haemorrhage induced by HLE, did not exhibit any effects due to the R and R1 substituents.

In a previous study we found that certain 3-phenylpiperidines (PPEs, 5) display a good activity at α2-adrenergic receptors (α2-AR ), whereas they are completely inactive at α1-AR. The PPEs 5 are conformationally restricted analogs of the corresponding adrenergic drug with a phenylethylamine structure (PAEs, 4) in which the benzylic hydroxyl group characteristic of the adrenergic catecholamines is not present. The most interesting of the PPEs proved to be the 3-(3,4-dimethylphenyl) substituted compound (5a) which had been found to be essentially inactive at β1- and β2-AR. The methyl groups present on the aromatic ring of 5a are found, albeit in a different position, on the phenyl of α2-adrenergic agonists with arylimidazolidine and arylimidazole structures. As such PPE 5a provided a unique template for the design of α2-AR ligands. On the basis of these premises, we synthesized all the possible dimethylphenyl-substituted isomers of PPE 5a. Their activity on α1- and α2-AR and on I1-imidazoline receptors (IR) was evaluated in vitro both by radioligand binding assays and by functional tests on isolated preparation. Two selected PPEs, 5a and 5f, were also tested for their affinity on α2-AR subtypes. Conformational studies were carried out by means of theoretical calculations, in order to rationalise the results of pharmacological tests at the molecular level.

Summary In order to contribute to the definition of the role played by the benzylic hydroxyl group of adrenergic catecholamines in eliciting α-adrenergic activity, certain 3-phenyl-3-piperidinols (PPOs, 4) and their corresponding desoxy 3-phenylpiperidine analogs (PPEs, 6) were synthesized and tested for their (α1- and α2-adrenergic activity by means of functional tests on isolated preparations. As regards the α1-adrenergic activity, the values of the activity indices of the cyclic catecholic compounds (PPO 4a and PPE 6a) indicate that the benzylic hydroxyl does not play an essential role, provided that the other two active groups are in the pharmacophoric conformation. However, the fact that none of the other non-catecholic cyclic analogs are active on the α1-receptor does not allow us to generalize this observation. As regards the α2-adrenergic activity, the high values of the activity indices of PPEs 6, compared with those of the corresponding 1-phenyl-2-aminoethanols (PAEs, 3), PPOs (4) and 2-phenylethylamines (PEAs, 5), confirm that when the aromatic moiety and the amino group are constrained into the pharmacophoric relationship, the presence of the alcoholic hydroxyl is not only unnecessary for the purposes of the expression of the activity at the level of the α2-adrenoceptor, but often has a negative effect.

Previous studies in the field of beta-adrenergic drugs had supported the hypothesis of the existence of a bioisosterism between the [(methyleneamino)oxy]methyl moiety (C = NOCH2, MAOMM) of type B beta-blocking drugs and the aryl (Ar) of type A beta-blocking agents. In the MAOMM, however, the carbon of the CH2 linked to the oximic oxygen possesses a hybridization (sp3) and a geometry different from those of the corresponding carbon of Ar which possesses an sp2 hybridization. Furthermore, in the MAOMM, in its preferred conformation, the unsaturated portion (C = N) is situated in a spatial area which does not correspond exactly to the area occupied by Ar. The formal inversion of the atomic sequence C = NOCH2 of the MAOMM leads to a different type of group, the [(methyloxy)imino]methyl moiety (CH2ON = C, MOIMM), which, in the E configuration, appears to present greater steric and electronic analogies with an Ar, with respect to the MAOMM. On the basis of these observations, some completely aliphatic (E)-N-(3-amino-2- hydroxypropylidene)(alkyloxy)amino derivatives of type C (11a,b and 12a, b) were synthesized, the their beta-adrenergic properties were compared with those of the corresponding [(methyleneamino)oxy]-methyl isomers of type B (19a, b and 20a, b). The similar beta-adrenergic properties of 11, 12 and 19, 20 evaluated in vitro both by radioligand binding assays and by functional tests on isolated preparations, are discussed on the basis of considerations regarding the spatial correspondences and electronic analogies between the MOIMM and the MAOMM.

The reaction of 4-[((p-nitrobenzoyl) oxy) methyl]-3-cephem derivative 4 with bromine in methanol afforded a mixture of the 3-bromo-4-methoxy adducts 5 and 6 and of the unexpected 4-spiro orthoesters 7 and 8. The structure and configuration of 7 and 8 were demonstrated through the determination of the solid-state structure of 7 and by 1 H and 13 C NMR studies and chemical transformations. The mechanism and the stereochemical outcome of the reaction are discussed

The 3-aminoxy-( E )-2-methoxyiminopropionyl penicillins 13 and cephalosporins 14 and 15 were synthesized and assayed for their antimicrobial activity on Gram-positive and Gram-negative bacteria whether producers of β-lactamases or otherwise. Compounds 13 , 14 , and 15 exhibited an activity which was generally lower than that of the corresponding phenylacetyl derivative: penicillin G ( 4 ), cephaloram ( 5 ), and phenylacetamidodesacetoxycephalosporanic acid ( 6 ). Furthermore, the comparison of the minimum inhibitory concentration values of some of the new 2-methoxyimino 3-aminoxypropionyl derivatives 13–15 with those of the corresponding ones 1–3 lacking the 2-methoxyimino substituent showed that the introduction of the 2-methoxyimino group of E configuration on the aminoxypropionamido side chain of 1–3 gives compounds ( 13–15 ) which do not generally possess better antimicrobial properties.

The cepham (9) and the penam (10) derivatives, with their carboxylic group in the “wrong” β-configuration, which is opposite to that exhibited by the common penicillins, were synthesized and assayed in vitro for antimicrobial properties. Compounds 9 and 10 , tested on Gram-positive and Gram-negative bacteria, both sensitive and resistant to β-lactamase inactivation, exhibited a very poor activity, directed only against non-β-lactamase-producing Gram-positive bacteria. One of the possible explanations for these results may be found in unfavourable steric and electronic effects deriving from the α-oriented methoxy group which is adjacent to the pharmacophoric carboxylic function.

Several (E)- and (Z)-N-alkyl-alpha,beta-dimethylcinnamamides variously substituted on the phenyl group were synthesized from their corresponding acids and characterized through their NMR spectra. The compounds were tested to determine the relationship existing between their action on the CNS and the activity exhibited by the corresponding amides unsubstituted on the phenyl, previously studied. Substitution with the same group always had the same effects on the biological activity of the (E)-N-alkyl-alpha,beta-dimethylcinnamamides selected; these effects mainly regarded anticonvulsant activity which is the most noteworthy action of these compounds. This activity was reduced by electron-donating substituents and increased by electron-withdrawing ones. In the Z series the p-phenyl substitution with a halogen reduced or suppressed the CNS stimulant activity exhibited by the parent compounds.

The electric dipole moments of some styrene and trans- and cis-stilbene oxides have been measured, in benzene. From these data some bond angles have been calculated and it has been deduced that in the styrene derivatives the phenyl group is in rapid interconversion about the bond with the triatomic ring.

The role of the aromatic moiety of beta-adrenergic drugs in the interaction with the receptor was investigated using the quantum mechanical ab initio SCF-MO-LCAO method. The structure-activity relationship was essentially discussed by analyzing the electrostatic molecular potential of three compounds which constitute meaningful portions of isoproterenol, INPEA, and doberol, the first drug having a stimulating activity and the others a blocking one. The results obtained point out the different roles played in the drug-receptor interaction by the various regions of the drugs and they also show that the aromatic moiety influences both the affinity and the intrinsic activity of the drugs. Indeed, the spatial correspondence among zones with negative potentials, which are localized on the phenyl substitutents of isoproterenol and INPEA and on the phenyl ring of doberol, could contribute to the affinity. On the other hand, the intrinsic activity of isoproterenol might be associated both with the proton-donor tendency of one phenolic OH group and with the wide zone of negative potential which spreads on a large part of the aromati moiety.

The 3-[(2-ethoxyphenoxy)methyl]piperidine derivatives 3-5 were synthesized and screened as potential antidepressant agents by the reserpine interaction test in mice and the evaluation of reuptake inhibition of biogenic amines in pig brain synaptosomal fractions. In addition, their anticonvulsant activity, tested by pentyleneetrazole antagonism, and approximate acute toxicity were evaluated. In vivo and in vitro tests showed that compounds 3 and 5 possess a biological activity comparable to that of the antidepressant drug viloxazine.

The cepham (9) and the penam (10) derivatives, with their carboxylic group in the “wrong” β-configuration, which is opposite to that exhibited by the common penicillins, were synthesized and assayed in vitro for antimicrobial properties. Compounds 9 and 10 , tested on Gram-positive and Gram-negative bacteria, both sensitive and resistant to β-lactamase inactivation, exhibited a very poor activity, directed only against non-β-lactamase-producing Gram-positive bacteria. One of the possible explanations for these results may be found in unfavourable steric and electronic effects deriving from the α-oriented methoxy group which is adjacent to the pharmacophoric carboxylic function.

A new transformation of Kamiya's disulphide ( 1 ) into the bromopenam derivative ( 4 ) has been carried out by electrolyzing the disulphide ( 1 ) in protic solvents in the presence of Me4NBr. The transformation occurs through an intermediate episulphonium-bromide ion pair in which the bromide appears to tightly linked to the sulphur.

The reaction of 1,2-epoxy-1-(p-nitrophenyl)cyclohexane with boron trifluoride–diethyl ether exhibits a pronounced solvent dependence: in benzene it gives a 9 : 1 ratio of cis-2-fluoro-2-(p-nitrophenyl)cyclohexanol to 1-(p-nitrophenyl)cyclopentanecarbaldehyde, which does not change with reaction time; in dichloromethane the cis-fluorohydrin is again the main primary product, but is rapidly converted into the aldehyde in the reaction medium; and in ether about equimolar amounts of cis- and trans-2-fluoro-2-(p-nitrophenyl)cyclohexanol are formed. The presence of small amounts of water in the dichloromethane solvent causes the formation of a ca. 6 : 4 mixture of cis-fluorohydrin and aldehyde, the composition of which changes little with reaction time. This solvent dependence of the reaction can be useful for preparative purposes. A reaction mechanism is suggested.

The crystal structure of the title compound (4) has been determined by three-dimensional diffraction methods. Crystals are orthorhombic, space group P212121 with Z= 4, unit cell dimensions a= 23.771(7), b= 8.833(2), c= 7.943(7)A. The structure has been solved by direct methods and refined by least-squares to R 0.051. The relevant molecular parameters are compared with those of other Δ3-cephem derivatives. In particular the same distortions of the β-lactam ring are observed; the lactam-nitrogen atom is out of the plane of its bonded carbon atoms by 0.20 A.

Two kinds of cyclic analogues of norepinephrine (NE, 7) and isoprenaline (ISO, 8), in which the C(1)-C(2) side chain of these amino alcohols is incorporated in its preferred conformation in the ring of the 2-(3,4-dihydroxyphenyl)-morpholines 9 and 10 (2-DPMs) and in the ring of the 3-(3,4-dihydroxyphenyl)-3-piperidinols 11 and 12 (3-DPPs), respectively, were synthesized and assayed for their adrenergic activity on various isolated preparations. The 2-DPMs and the 3-DPPs showed an alpha- and beta-agonist activity comparable to that of NE and ISO and to that of the trans-2-amino-5,6-dihydroxytetrahydronaphthalen-1-ols 13 and 14 (2-ADTNs), which represent another kind of semirigid analogue of NE and ISO. Through a comparison of the stereo structures of the compounds examined and of their pharmacological properties, it was possible to suggest a spatial situation in which the pharmacophoric groups of the adrenergic drugs examined (aryl moiety, amine nitrogen, and alcoholic or ethereal benzylic oxygen) should interact at the receptor site. This spatial situation corresponds to the one found in the preferred conformation of NE and ISO. It was also possible to construct two theoretical three-dimensional molecular models that provide information about steric requirements for the direct activation of alpha- and beta-adrenoceptors, respectively.

endo-3-Amino-exo-2-(3,4-dihydroxyphenyl)-2-hydroxybicyclo[2.2.1]he ptane (4a) and its N-isopropyl derivative (4b) were synthesized and assayed for their adrenergic activity on various isolated preparations. Compounds 4a and 4b, tested up to a dose of 10(-4) M, did not reveal any activity, either stimulant or blocking, on the alpha- and beta-adrenoceptors. Possible rationalizations of the results obtained, however, are suggested.

The shielding effects of some substituents on the chemical shifts of the methine proton of axial and equatorial cyclohexanols have been calculated and rationalised. The remarkable downfield shift observed for the phenyl substituent has been discussed on the basis of Johnson-Bovey and Haigh-Mallion theories. The chemical shift of methine protons of some cyclohexanols have been calculated using additive shielding increments. Agreement between calculated and experimental values substantiates the use of the additivity principle in cyclohexyl systems and justifies the origin of certain marked inversions of the accepted rule that the axial protons resonate at lower fields than the corresponding equatorial ones.

The trans and cis forms of 3- and 4-stillbazole oxide and trans -2-( p -methoxystyryl)pyridine oxide have been prepared from the corresponding stilbazoles, by addition of HClO and HBrO, followed by dehydrohalogenation of the halohydrins with base. The configurations of the epoxides have been confirmed by their NMR spectra. The stereochemistry of the ring opening of the above mentioned compounds with HCl, HBr and CCl 3 COOH has been investigated and compared with that of the similar reactions of the stilbene oxides, very pronounced differences in steric course being observed. The reactions of the stilbazole oxides with the hydrogen halides take place with complete inversion, those with CCl 3 COOH with decreasing degrees of inversion in going from the 2- to the 3- and to the 4-pyridyl derivatives.