Monte A P, Marona-Lewicka D, Lewis M M, Mailman R B, Wainscott D B, Nelson D L, Nichols D E
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy, Purdue University, West Lafayette, Indiana 47907, USA.
J Med Chem. 1998 Jun 4;41(12):2134-45. doi: 10.1021/jm980076u.
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.
合成了一系列取代的外消旋萘并呋喃，作为两种主要原型致幻药物类别（苯乙胺类和色胺/麦角碱类）的“杂合”分子。尽管据推测这些新化合物可能对5-羟色胺5-HT2A/2C受体亚型具有高亲和力，但却观察到它们对毒蕈碱受体具有意外的亲和力。最初为该研究合成的化合物分别是（±）-反式和顺式-4-氨基-6-甲氧基-2a，3，4，5-四氢-2H-萘并[1，8-bc]呋喃（4a，b），以及它们的8-溴衍生物4c，d。最初对溴代伯胺4c，d在训练用于区分盐水和酒石酸LSD（0.08mg/kg）的大鼠的双杠杆药物辨别（DD）范式中的活性进行了测定。此外，还评估了4c，d在克隆的人5-HT2A、5-HT2B和5-HT2C受体上与激动剂和拮抗剂放射性配体竞争的能力。在这些初步试验中发现顺式非对映异构体具有最高活性后，制备了N-烷基化类似物顺式-N，N-二甲基-4-氨基-6-甲氧基-2a，3，4，5-四氢-2H-萘并[1，8-bc]呋喃（4e）和顺式-N，N-二丙基-4-氨基-6-甲氧基-2a，3，4，5-四氢-2H-萘并[1，8-bc]呋喃（4f）并测定它们在[3H]酮色林标记的5-HT2A和[3H]-8-OH-DPAT标记的5-HT1A位点的亲和力。所有测试的分子对5-羟色胺受体的亲和力相对较低，但初步筛选表明化合物4d对毒蕈碱受体具有亲和力。因此，评估了4b，d，e在毒蕈碱M1-M5受体上的亲和力，并在M1和M2亚型上评估了它们的功能特性。化合物4d在所有毒蕈碱位点的亲和力为12-33nM，4b，e的亲和力则低得多。所有三种化合物在M1受体上完全拮抗卡巴胆碱的作用，而只有4d在M2受体上完全拮抗卡巴胆碱的作用。萘并呋喃缺乏类似LSD的活性这一事实表明，它们与5-羟色胺受体的结合方式使得三环萘并呋喃核与LSD的A、B和C环不是生物电子等排体，也不能直接叠加。因此，这也意味着，与先前的假设相反，这两类化学物质在共同的结合取向上，致幻苯乙胺不能直接叠加在LSD上。
