Sites, mechanisms, and structural characteristics of the brain's nicotine receptor.

Studies are described dealing with the molecular features of nicotine, the receptor binding and psychotropic properties of nicotine agonists and antagonists, and the neuroanatomical locus of action of nicotine associated with its psychotropic action. Bridged analogues of nicotine have been developed to define the optimal conformation of the molecule for maximal receptor affinity and psychotropic action in rats. With another series of analogues, it was demonstrated that contraction of the pyrrolidine ring to a 4-member azetidine enhances potency while expansion diminishes it. A major site for nicotine's central action is the vestibular cerebellum as demonstrated by kainic acid lesioning studies and direct administration of nicotine into this region. Included among the antagonists to nicotine was alpha-lobeline, which appeared to be a mixed agonist-antagonist.

Synthesis and biological characterization of pyridohomotropanes. Structure-activity relationships of conformationally restricted nicotinoids.

The recently discovered nicotinic agonist pyrido[3,4-b]norhomotropane [corrected] (PHT) as well as its N-methyl and 2'-methyl derivatives (syntheses reported herein) were compared with nicotine, nornicotine, and anatoxin a in a series of in vitro and in vivo assays. The results reveal that PHT possesses activity comparable to that of the highly potent agonist, anatoxin a. The inactivity observed relative to PHT of N-methyl- and 2'-methyl-PHT has helped to further define the structure-activity requirements of conformationally restricted nicotinoids.

8-Methoxypsoralen-nucleic acid photoreaction. Effect of methyl substitution on pyrone vs. furan photoaddition.

We have synthesized a series of 8-[3H]methoxypsoralens in which methyl and hydrogen are systematically varied at the 4- and 5'-positions. Analysis of the products resulting from the photoaddition of these four psoralens with the nucleic acid poly(dA-dT) reveals that the product distribution depends on the presence or absence of a 4-methyl substituent. Compounds with the 4-methyl group show an overwhelming preference (approximately 98%) for addition to the furan double bond, while compounds without the 4-methyl show a substantial amount (approximately 18%) of addition to the pyrone double bond.

Psoralen-deoxyribonucleic acid photoreaction. Characterization of the monoaddition products from 8-methoxypsoralen and 4,5'8-trimethylpsoralen.

The isolation and structural characterization are described of the major monoaddition products formed in the photoreaction of two naturally occurring psoralens, 8-methoxypsoralen and 4,5',8-trimethylpsoralen, with high molecular weight, double-stranded DNA. Hydrolysis of the psoralen-modified DNA and subsequent chromatography resulted in the isolation of four modified nucleosides from each psoralen. Structural characterization was accomplished by mass spectrometry and 1H NMR analysis. The major products, accounting for 44-52% of the covalently bound psoralen, are two diastereomeric thymidine adducts formed by cycloaddition between the 5,6 double bond of the pyrimidine and the 4',5' (furan) double bond of the psoralen. A minor product, less than 2% of the covalently bound psoralen, is a furan-side adduct to deoxyuridine, derived from an initially formed deoxycytidine adduct by hydrolytic deamination. A fourth product is a thymidine adduct where cycloaddition has taken place between the 5,6 double bond of the pyrimidine and the 3,4 (pyrone) double bond of the psoralen. This pyrone-side adduct accounts for 19% of the covalently bound 8-methoxypsoralen but for less than 3% of the covalently bound 4,5'8-trimethylpsoralen. All of the isolated adducts have cis-syn stereochemistry. The stereochemistry and product distribution of the adducts are determined in part by the constraints imposed by the DNA helix on the geometry of the noncovalent intercalation complex formed by psoralen and DNA prior to irradiation.