Linked Life Data

9622555

Source:http://linkedlifedata.com/resource/pubmed/id/9622555

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
12
pubmed:dateCreated
1998-6-24
pubmed:abstractText
A series of substituted racemic naphthofurans were synthesized as "hybrid" molecules of the two major prototypical hallucinogenic drug classes, the phenethylamines and the tryptamines/ergolines. Although it was hypothesized that these new agents might possess high affinity for the serotonin 5-HT2A/2C receptor subtypes, unexpected affinity for muscarinic receptors was observed. The compounds initially synthesized for this study were (+/-)-anti- and syn-4-amino-6-methoxy-2a,3,4,5-tetrahydro-2H-naphtho[1,8-bc]furan (4a,b), respectively, and their 8-bromo derivatives 4c,d, respectively. The brominated primary amines 4c,d were assayed initially for activity in the two-lever drug discrimination (DD) paradigm in rats trained to discriminate saline from LSD tartrate (0. 08 mg/kg). Also, 4c,d were evaluated for their ability to compete against agonist and antagonist radioligands at cloned human 5-HT2A, 5-HT2B, and 5-HT2C receptors. After the syn diastereomers were found to have the highest activity in these preliminary assays, the N-alkylated analogues syn-N,N-dimethyl-4-amino-6-methoxy-2a,3,4, 5-tetrahydro-2H-naphtho[1,8-bc]furan (4e) and syn-N, N-dipropyl-4-amino-6-methoxy-2a,3,4,5-tetrahydro-2H-naphtho[1, 8-bc]furan (4f) were prepared and assayed for their affinities at [3H]ketanserin-labeled 5-HT2A and [3H]-8-OH-DPAT-labeled 5-HT1A sites. All of the molecules tested had relatively low affinity for serotonin receptors, yet a preliminary screen indicated that compound 4d had affinity for muscarinic receptors. Thus, 4b,d,e were evaluated for their affinity at muscarinic M1-M5 receptors and also assessed for their functional characteristics at the M1 and M2 isoforms. Compound 4d had affinities of 12-33 nM at all of the muscarinic sites, with 4b,e having much lower affinity. All three compounds fully antagonized the effects of carbachol at the M1 receptor, while only 4d completely antagonized carbachol at the M2 receptor. The fact that the naphthofurans lack LSD-like activity suggests that they do not bind to the serotonin receptor in a way such that the tricyclic naphthofuran nucleus is bioisosteric with, and directly superimposable upon, the A, B, and C rings of LSD. This also implies, therefore, that the hallucinogenic phenethylamines cannot be directly superimposed on LSD in a common binding orientation for these two chemical classes, contrary to previous hypotheses.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jun
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:day
4
pubmed:volume
41
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
2134-45
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed-meshheading:9622555-Animals, pubmed-meshheading:9622555-Binding, Competitive, pubmed-meshheading:9622555-Brain, pubmed-meshheading:9622555-Cell Line, pubmed-meshheading:9622555-Cricetinae, pubmed-meshheading:9622555-Discrimination Learning, pubmed-meshheading:9622555-Ergolines, pubmed-meshheading:9622555-Furans, pubmed-meshheading:9622555-Hallucinogens, pubmed-meshheading:9622555-Humans, pubmed-meshheading:9622555-Lysergic Acid Diethylamide, pubmed-meshheading:9622555-Male, pubmed-meshheading:9622555-Mice, pubmed-meshheading:9622555-Muscarinic Antagonists, pubmed-meshheading:9622555-Phenethylamines, pubmed-meshheading:9622555-Rats, pubmed-meshheading:9622555-Rats, Sprague-Dawley, pubmed-meshheading:9622555-Receptors, Muscarinic, pubmed-meshheading:9622555-Receptors, Serotonin, pubmed-meshheading:9622555-Recombinant Proteins, pubmed-meshheading:9622555-Stereoisomerism, pubmed-meshheading:9622555-Structure-Activity Relationship, pubmed-meshheading:9622555-Tetrahydronaphthalenes
pubmed:year
1998
pubmed:articleTitle
Substituted naphthofurans as hallucinogenic phenethylamine-ergoline hybrid molecules with unexpected muscarinic antagonist activity.
pubmed:affiliation
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy, Purdue University, West Lafayette, Indiana 47907, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S.