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At least 325 records · Page 18Linked to original sources
PubMed1993

Tröger's base. An alternate synthesis and a structural analog with thromboxane A2 synthetase inhibitory activity.

The synthesis of 2,8-dimethyl-6H,12H-5,11-methanodibenzo[b,f][1,5]diazocine (Tröger's base) from p-toluidine and of two Tröger's base analogs from other anilines by reaction with hexamethylenetetramine in trifluoroacetic acid is described. 2,3,6,7-Tetrahydro-9-methyl-2,6-di-p-tolyl-1H,5H-pyrimido[5,6,1-ij] quinazoline is formed as a secondary product in the reaction of p-toluidine and hexamethylenetetramine. One of the Tröger's base analogs, 2,8-bis(3'-pyridylmethyl)-6H,12H-5,11-methanodibenzo[b,f][1,5]d iazocine (5), is an effective inhibitor of the enzyme, thromboxane A2 (TxA2) synthase, with an ED50 of 30 ng/mL in a specified in vitro assay. Three analogs having substituents on the bridging methylene group of the bicyclic nucleus of the Tröger's base structure were prepared, but all were considerably less active than the aforementioned compound in the inhibition assay. The structures of these inhibitors of TxA2 synthase fall outside the classical structure-activity relationship that has been established for this class of enzyme inhibitors.

Azocines↗
PubMed1986

The ensemble approach to distance geometry: application to the nicotinic pharmacophore.

We develop an extension of conventional distance geometry techniques that treats two or more molecules as a single "ensemble". This extension can be used to find a common pharmacophore, i.e., the spatial arrangement of essential groups, from a small set of biologically active molecules. The approach can generate, in one step, coordinates for the set of molecules in their "active" conformations such that their essential groups are superimposed. As an example, we show how the nicotinic pharmacophore can be deduced from a set of four nicotinic agonists: nicotine, cytisine, ferruginine methiodide, and muscarone. Three essential groups in each agonist are chosen: the cationic center (A), an electronegative atom (B), and an atom (C) that forms a dipole with B. There is only one pharmacophore possible for the superposition of these essential groups: a triangle with sides 4.8 A (A-B), 4.0 A (A-C), and 1.2 A (B-C). The pharmacophore triangle, which is consistent with previous models in the literature, can also be achieved by the agonist trans-3,3'-bis[(trimethylammonio)methyl]azobenzene and the antagonists strychnine, trimethaphan, and dihydro-beta-erythroidine. An examination of the common volumes of agonists suggests a specific disposition of molecular volume relative to the pharmacophore triangle. We discuss the relative strengths and drawbacks of the ensemble approach vs. other conformational search methods.

Alkaloids↗
PubMed1986

Preparation and analgesic activity of (-)-11 alpha-substituted 1,2,3,4,5,6-hexahydro-6 alpha,7-(methyleneoxy)-2,6-methano-3-benzazocines.

Dihydrocodeinone oxime (1) under Beckmann rearrangement conditions gave a product (2) that facilitated the preparation of (-)-11 alpha-substituted 1,2,3,4,5,6-hexahydro-6 alpha,7-(methyleneoxy)-2,6-methano-3-benzazocines, a hitherto little-examined series of morphine partial structures. Compounds 7a and 12 gave good levels of agonist antinociceptive activity. Masking of the 8-oxygen function, as in 6 and 8, dramatically reduced mouse hot-plate activity, as did its loss (9).

Analgesics, Opioid↗
PubMed1979

(2,6-Methano-3-benzazocin-11 beta-yl)alkanones. 1. Alkylalkanones: a new series of N-methyl derivatives with novel opiate activity profiles.

A general stereospecific synthesis of (N-methyl-2,6-methano-3-benzazocin-11 beta-yl)alkanones is described and applied to the preparation of a series of alkyl ketones wherein the alkyl group is a straight or terminally branched chain containing from one to six carbon atoms. Several compounds with methoxy groups in the aromatic ring are in the morphine range of potency; they are uniformly inactive as phenazocine antagonists. Phenolic analogues range up to 100 times as potent as morphine. Those containing five or six carbon atoms in the alkyl group exhibit phenazocine antagonist activity, in one case equivalent to naloxone. This compound (3e) is selective for phenazocine in its antagonist action.

Analgesics, Opioid↗
PubMed1978

3-Benzazocine amidinium nitronates. An unusual type of opiate antagonist.

An interesting type of 3-benzazocine ring system which contains amidine functionality has been found to have significant narcotic antagonist activity. The isomeric 2-benzazocine, which incorporates similar structural features, except for the position of the ring nitrogen and adjacent phenyl substituent, is inactive. These 2- and 3-benzazocines can be synthesized in a single step from appropriately structured amidines and naphthalenes, and such syntheses may provide useful routes to new and interesting types of narcotic antagonists.

Amidines↗
PubMed1978

2,6-Methano-3-benzazocine-11-ropanols. Lack of antagonism between optical antipodes and observation of potent narcotic antagonism by two n-methyl derivatives.

Resolution of a 2,6-methano-3-benzazocine-11-propanol analogue of buprenorphine showed that the biological activity resides in the levo antipode. An attempt to enhance agonist activity by preparation of N-methyl derivatives resulted in two compounds three and five times as potent as nalorphine as antagonists of phenazocine. These compounds are the most potent N-methyl narcotic antagonists reported to date.

Animals↗
PubMed1977

9-hydroxy-1,2,3,4,5,6-hexahydro-1,5-methano-3-benzazocine derivatives as analgesics.

Three 1,3-dimethyl-9-hydroxy-1,2,3,4,5,6-hexahydro-1,5-methano-3-benzazocine derivatives (7-9) have been synthesized and tested as analgesics. The synthesis of these compounds involved conversion of 1-methyl-7-methoxy-beta-tetralone (1) by Mannich reaction with MeNH2 and HCHO to give the 11-ketone 2, from which 7,8, and 9, respectively, were obtained. These compounds have analgesic activity, and 7 was found to be comparable to codeine.

Analgesics↗
PubMed1977

Narcotic antagonists. Synthesis and evaluation of some subsituted 1,2,3,4,5,6-hexahydro-1,4:2,6-dimethano-3-benzazocines.

A seres of (+/-)-N-substituted 6-ethyl-or -methyl-8-hydroxy-1,2,3,4,5,6-hexahydro-1,4:2,6-dimethano-3-benzazocines has been prepared from 6 hydroxytropinone. The N-cyclopropylmethyl compounds 10a and 10b were found to be strong narcotic antagonists approximately equivalent to nalorphine. Only slight analgetic activity was found in any of these compounds including the two N-methyl analogues.

Analgesics↗
PubMed1977

Synthesis and narcotic agonist-antagonist evaluation of some 2,6-methano-3-benzazocine-11 propanols. Analogues of the ring C bridged oripavine-7-mehtanols.

A general synthesis of variously substituted 2,6-methano-3-benzazocine-11-propanols is described. Nine N-CH3 derivatives and their corresponding N-cyclopropylmethyl counterparts were prepared and studied in the mouse acetylcholine induced writhing and rat phenazocine antagonism tests. The results are compared with literature information on the bridged oripavine methanols. It is concluded that the synthetic analogues have a different structure-activity profile, in general being weak agonists but potent antagonists.

Acetylcholine↗
PubMed1975

Analgetic activity and in vitro binding constants of some N-alkyl-3-benzazocines.

A homologous series of 3-alkyl-1,2,3,4,5,6-hexahydro-8-hydroxy-6-methyl-3-benzazocines (2) has been synthesized. Analgetic activity and binding constants for the opiate receptor for 2 and for an analogous series of benzomorphans (1 and 3) are reported. In 1, hot-plate analgesic activity is lost on increase of the N-alkyl chain length from ethyl through butyl (lc-e) and regained with amyl (lf) and hexyl (lg). Compounds lc-e show that antagonist properties and binding constants are similar throughout the series. With 2, where there has been loss of steric constraints through removal of the 2,6-methano bridge of 1 and 3, greatly diminished analgetic activity and receptor affinity and no antagonist properties were observed. Like 1, however, greatest agonist activity was shown by the N-methyl (2c), amyl (2g), hexyl (2h), and heptyl (2i) homologs and there is a parallel of in vitro binding strength and analgetic activity.

Analgesics↗