SUBSTITUTED NAPHTHOFURANS AS HALLUCINOGENIC PHENETHYLAMINE-ERGOLINE HYBRID MOLECULES WITH UNEXPECTED MUSCARINIC ANTAGONIST ACTIVITY

A series of substituted racemic naphthofurans were synthesized as ''hy brid'' molecules of the two major prototypical hallucinogenic drug cla sses, the phenethylamines and the tryptamines/ergolines. Although it w as hypothesized that these new agents might possess high affinity for the serotonin 5-HT2A/2C receptor subtypes, unexpected affinity for mus carinic receptors was observed. The compounds initially synthesized fo r this study were (+/-)-anti- and methoxy-2a,3,4,5-tetrahydro-2H-napht ho[,8-bc]furan (4a,b), respectively, and their 8-bromo derivatives 4c, d, respectively. The brominated primary amines 4c,d were assayed initi ally for activity in the two-lever drug discrimination (DD) paradigm i n 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-HT2 C receptors. After the syn diastereomers were found to have the highes t activity in these preliminary assays, the N-alkylated analogues etho xy-2a,3,4,5-tetrahydro-2H-naphtho[1,8-bc]furan (4e) and ethoxy-2a,3,4, 5-tetrahydro-2H-naphtho[1,8-bc]furan (4f) were prepared and assayed fo r their affinities at [H-3]ketanserin-labeled 5-HT2A and [H-3]-8-OH-DP AT-labeled 5-HT1A sites. All of the molecules tested had relatively lo w 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 M-1-M-5 receptors and also assessed for their functional characteristics at the M-1 and M-2 isoforms. Compound 4d had affinities of 12-33 nM at all of the muscari nic sites, with 4b,e having much lower affinity. All three compounds f ully antagonized the effects of carbachol at the M-1 receptor, while o nly 4d completely antagonized carbachol at the M-2 receptor. The fact that the naphthofurans lack LSD-like activity suggests that they do no t bind to the serotonin receptor in a way such that the tricyclic naph thofuran nucleus is bioisosteric with, and directly superimposable upo n, the A, B, and C rings of LSD. This also implies, therefore, that th e hallucinogenic phenethylamines cannot be directly superimposed on LS D in a common binding orientation for these two chemical classes, cont rary to previous hypotheses.