Morphans

Another characteristic of PCP which has been studied with great interest over the last 5 years, is the ability of PCP to produce a discriminative stimulus in monkeys, rats, and pigeons. As discussed elsewhere in this volume, by Browne, the discriminative stimulus properties of PCP are shared not only by other members of the arylcycloalkylamine class, but by psychotomimetic benzo-morphans and substituted dioxolanes. The structure-activity relationships (SAR) within and between these classes are virtually identical to those found when studying the displacement of 3H-PCP from its binding site in rat brain membranes. This correlation... 

It has been proposed, on the basis of observations made using the benzo-morphan derivative (MR 2034) (8), that all kappa agonists may cause undesired dysophoria and even psychotomimesis in man [27]. Benzomorphans such as MR 2034 with affinity for sigma receptors are well-known to be associated with dysphoria. To date, there has been no report of a dose-ranging clinical study with a truly kappa selective agonist which describes the analgesic effects and the onset of dysphoric symptoms. 

Hydroxy-N-Methylisomorphinan. 24 mg of the 3-hydroxy-delta-6-dehydro-N-methyl-morphan is hydrogenated over 5 mg of Adams catalyst in 15 cc of dcohol. H2 uptake is complete after 35 min. The solution is filtered, concentrated, and the residue is ciystallized from benzene to yield 24 mg of colorless fine prisms. 

The derivatives of 2-azabicyclo[3.3.1]nonanes (morphane) (41) can also be used to build the framework of alkaloids with the azocino[4,3-l7]indole fragment. 7-(2-Nitrophenyl)-substituted azabicyclononanone 42 obtained from N-benzylpiperidone-4 (seven stages, total yield (10%)) under the conditions of reductive cyclization has been converted into N-benzylhexahydroazocino [4,3-1 ]-indole 43 (Scheme 10 88T2087). 

The Fischer indolization of bicycloketones of the morphane series often has been used for the synthesis of the corresponding azocinoindoles (89TL3841, 90TL2449, 92LA461). Thus, bicyclic ketone 44, under Fischer conditions, has been transformed into azocinoindole 45 in moderate yields (94JOC3939 Scheme 11). 

In recent years much attention has been paid to the synthesis of benzomorphane heteroanalogs in which a benzene ring has been replaced by a heteroaromatic one. Syntheses of substituted thieno[3,2-/]morphanes (derivatives of thieno[2,3-d]-azocine) described in Ref. 75JHC651 consists of the condensation of cyanopyri-dines 120 with 2-thienyllithium, reduction of the resulting ketones into thienylmethylpyridines, quaternization and reduction of the quaternary salts with sodium borohydride to form piperidines 124 and 125. Intramolecular cyclization of the latter leads to the formation of thieno[2,3-d]azocines 126 (Scheme 34). 

Intramolecular alkenic cyclization has been utilized to prepare thieno[2,3-/]morphan and thieno[3,2-/]morphan (74JHC853, 75JHC651). 

Pentazocine is a potent analgesic of the benzo-morphan series with a 50 rag oral dose equivalent to 60 rag of codeine. It is also a weak narcotic antagonist with about one-fiftieth the activity of nalorphine. Pentazocine is indicated in the treatment of moderate to severe pain. It is also used as a preanesthetic and anesthetic supplement (1,2). 

A range of polycyclic benzo b furans illustrated below was formed by the CuI/TMEDA mediated coupling reaction of conjugated aryl bromide-alkenyl triflates <07TL7578>, and a similar reaction was also found in the synthesis of 5-phenyl morphans <07H(71)881>. 

Activities no greater than that of morphine have been observed in benzo-morphans bearing 2-, 4-, or 5-substituents, and in general, substitution in these positions tends to reduce responses in 6-alkyl and 6,11-dialkyl species (p. 193). 

Several benzomorphan series have now been resolved into their (-)- and (+)-antipodes, and ORD/CD studies (p. 204) have demonstrated that (-)-series have a configuration identical to (-)-morphine. In addition, Sawa et aL(202,203) [lave prepared (—)- and (+)-8-hydroxyl-3-methyl-6,ll-diethylbenzo-morphans from thebaine and sinomenine, respectively. It is largely in the (-)-series that narcotic properties reside, but some curious activities are seen in (+)-series. 

In the previous chapter benzomorphan analgesics were considered. They may be thought of as sterically constrained piperidines bearing an axial aromatic ring. Without the fused aromatic ring a 2-azabicyclo[3.3.1]nonane structure (1) remains for which the trivial name morphan was suggested by Robinson/0... 

Clearly, aryl groups may be positioned on the morphan nucleus in several positions to afford possible analgesic relationships for the nitrogen and aromatic pharmacophores. There have been relatively few studies of arylmorphans and related structures those compounds with aryl substituents at C-5 (i.e., equatorial on a partially constrained piperidine) have received most attention. 

A comparison of the absolute configurations of (-)-5b and morphine is not possible because of the difference in the orientation of their aromatic rings. Cochran<7) investigated the absolute configuration of (—)-5-(3-hydroxyphenyl)-2-methylmorphan by single-crystal, X-ray analysis of the HBr salt and found it to be 1R, 5S. He discovered that both rings of the morphan-fused system existed in chair conformations with the 2-methyl and 5-aryl substituents equatorial. 

A study of the limits of rotational mobility of the aromatic ring relative to the piperidine unit and commensurate with opioid pharmacological responses has been commenced at NIH.(34) The importance of the torsion angle between these moieties has been a point of comment in the prodine series/35 36 By formally joining the 2 position of the phenyl ring of a 5-arylmorphan to the 6-position of the morphan moiety, a rigid congener would result (24). The NIH synthetic pathway to such a compound is outlined in Scheme 5.5. The key step is a photocyclization from 22 to the partially reduced dibenzofuran 23. 

Displacement of the nitrogen from its morphan position, as in the 1-phenyl-3-azabicyclo[3.3.1]nonanes (29), afforded compounds without MW analgesic activity, but where, again, some antagonist activity was detected.(22)... 

The necessity for having an appropriately positioned aromatic ring on a morphan nucleus for narcotic analgesic activity has been demonstrated.(25) 2-Methylmorphan (32) and the corresponding 6- and 7-enes were found to be devoid of MHP activity. Several substituted analogs of 31 have been reported more recently. (38 40) Some of these were synthetic precursors ofbenzomorphan-like compounds with a heterocyclic A-ring. 

Oxygen-bridged phenyl morphans were synthesized by an intramolecular phenolic hydroxyl based S 2 displacement of bromine as shown below <03T4603>. Two other phenylmorphans were also synthesized by almost identical conditions <03HCA484>. Closely related benzo[i>]furan based oxaspirocyclic molecules were made by a similar approach <03TL2971>. 

Bromat Cetab Cetavlon Cetraol Lissolamine V Mtcol Morpan CHSA Morphans Quammonium Sucticide. 

Randic, M. and Wilkins, C.L. (1979d). Graph Theoretical Study of Structural Similarity in Benzo-morphans. Int.J.Quantum Chem.Quant.Biol.Symp., 6, 55-71. 

Grewe, in 1946, approached the problem of synthetic analgesics from another direction when he synthesized the tetracyclic compound that he ftrst named morphan and then revised to A(-mcthylmorphinan. The relationship of thiseom-pound to morphine is obvious. 

OH, 30) (111), and TIPPm (Tyr-Tic [CHgNHlPhe-PheOH, 31) (112), and the nonpeptide naltrindole (32) (113). Recently, however, TIPP has been reported to exhibit agonist activity in adenylyl cyclase assays (114). Early studies of k receptors used benzo-morphans such as ethylketocyclazocine (EKC, 33), a close analog of ketocyclazocine, and bremazocine(34) (Fig. 7.6), but the selectivity of these ligands for k receptors is very low (see Table 7.8 below). Kappa-selective agonists such as U50,488 (35) (115), U69,593 (36) (116), and CI-977 (37) (117, 118), and the... 

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