Index
AIDA, 495 Affinity labeling, analogs of (Cont.) cAMP, 409, 489 motphine,448 ATP, 409, 489 naltrexone, 449 [3H] ATP, 489 norlevotphanol,449 Absolute configuration normetazocine, 181 benzomotphans, 204 norpethidine, 232 levotphanol, 115 oripavine, 453 methadone and analogs, 316 oxymotphone, 449 motphine, 86 K-Agonists, 179,405,434 phenoperidine, 234 Aid in Interactive Drug Analysis, 495 piperazine derivatives, 399 [L-Ala2] dermotphin, 363 prodines and analogs, 272 [D-Ala, D-Leu] enkephalin (DADL), 68, 344 sinomenine, 28, 115 [D-Ala2 , Bugs] enkephalinamide, 347, 447 viminol, 400 [D-Ala2, Met'] enkephalinamide, 337, 346, Ac 61-91,360 371,489 Acetylcholine, 5, 407 [D-Ala2]leu-enkephalin, 344, 346, 348 Acetylcholine analogs, 186, 191 [D-Ala2] met-enkephalin, 348 l-Acetylcodeine, 32 [D-Ala2] enkephalins, 347 Acetylmethadols (a and (3) Alfentanil, 296 maintenance of addicts by a-isomer, 304, 309 (±)-I1(3-Alkylbenzomotphans, 167, 170 metabolism, 309 11(3-Alkylbenzomotphans, 204 N-allyl and N-CPM analogs, 310, 431 7-Alkylisomotphinans, 146 stereochemistry, 323 N-Alkylnorketobemidones, 431 synthesis, 309 N-Alkylnorpethidines, 233 X-ray crystallography, 327 N-Allylnormetazocine, 420 6-Acetylmotphine, receptor binding, 27 N-Allylnormotphine, 405 Acetylnormethadol, 323 N-Allylnorpethidine, 233 8(3-Acyldihydrocodeinones, 52 3-Allylprodines (a and (3), 256 14-Acyl-4,5-epoxymotphinans, 58 'H-NMR and stereochemistry, 256 7-Acylhydromotphones, 128 X-ray crystallography, 256 Addiction, 4 N-Allylnormetazocine, 420 Adenylate cyclase, 6, 409, 413, 424, 453, 489- 6-Allyl-ll-oxobenzomotphan, 186 490 N-Allyl-D-Ala2 -metenkephalin, 434 Adrenal medulla, source of opioid peptides, 362 N-Allyl-Ieu-enkephalin, 434 Adrenergic receptors, 454 6-Allylbenzomotphans, 141 Affigel-401, 453 N-Allylcodeine (N-allylnorcodeine), 30, 405 Affinity chromatography, 448 (±)-N-Allylmethoxyhasubanan, 144 Affinity labeling, analogs of, 449 N-Allylnorketobemidone, 275 enkephalins, 348, 454 N-Allylnormetazocine, 176 fentanyl, 453 N-Allylnormotphine, 30 503 504 Index
Alvodine, 232 5-Arylmorphans (Cont.) 14-Amidomorphine, 430 pharmacology, 216 Amidone, 303 ( + )-5R-isomers, 226 6-Amino-3,3-diphenylhexan-3-one, 307 stereochemistry, 216 9-Aminoarylmorphans, 219 N-substituted, 218 8-Aminobenzomorphans, 182 synthesis, 215 I-Aminocodeine, 32 3-Arylpiperidines, 432, 433, 468, 474 t-Aminocyclohexanes, 395 4-Arylpiperidines, 299,473,474,476,481- w-Aminohexyl septarose, 448 485 14!3-Aminomorphine, 448 4-alkyl, 432 Aminopeptidases, 337 antagonists, 431 N-p-Aminophenethylnorpethidine, 232 aromatic group variation, 240 Aminotetralins, 396,464 phenolic, 276 Aminotetralins, bridged, 433 3-Arylpyrrolidines, 433, 474 Amitriptyline, 236 2-Arylthiobenzimidazoles, 389 Androcymbine, 145 Aspirin, 1,312 Anileridine, 232, 449 Autoradiography, 446, 490 4-Anilido-I-phenethylpiperidine, 485 Azabicylanes, 483 4-Anilidopiperidines, 466 Azabicyclo [2.2.1] heptanes, 245 4-Anilinopiperidines, 287 2-Azabicyclo [2.2.2] octanes, 298 4-Anilinopiperidines, QSAR, 297 Azabicyclo [3.2.1] nonanes, 215 Animal test procedures, 2 Azacycloalkanes, 251 Antagonists opioid, 405 Azacycloheptan-4-one, 244 basic nitrogen and C-14 substituents, 9-Azamorphinans, 143 424 6-Azido-4,5-epoxymorphinans,92 benzomorphan derivatives, 420, 424 Azidomorphines, 39 K-antagonists, 434 N-!3-(p-Azidophenyl)ethylnorlevorphanol, 119 morphinan derivatives, 416, 427 morphine derivatives, 409 BAM-l2P, 20P, 22P, 362 non-morphine based, 431 BIT, 388,453,492 pure, 412 BSA,446 SARs, 409 Bacitracin, 337, 350 Antinociceptive tests for opioid agonists, 2 Barbiturates, 1, 460 [Arg6]leu-enkephalin, 361 Basic nature of opioid ligands, 460 N-Arginyl-metenkephalin, 180, 372 N-substituent structure, 466 Aromatic features of opioid ligands, 467 Basic propionanilides, 311 4-Aryl-4-alkylpiperidines, 276, 432, 469 conformation (X-ray), 322 synthesis, 279 synthesis, 321 3-Aryl-3-alkylpyrrolidines, 244 Beckett -Casy hypothesis, 471 4-Ary 1-4-dimethy laminocyclohexanols, 391 Beckmann rearrangement, 195, 216 3-Aryl-3-methylpiperidines, 245, 279, 432 Belleau's lone-pair hypothesis, 464 pyrrolidine analogs, 281, 433 Belleau's single receptor theory, 456 synthesis, 380 Bemidone, 239, 241 4-Aryl-4-piperidinols, synthesis, 240 antagonist analog, 431 6-Aryl-2-azabicyclo [4.3.1] decanes, 226 3-Benzazocine-2-carbonitrile, 195 1-Aryl-6-azabicyclo [3.2.1] octanes, 223 Benzethidine, 235 4-Aryl-2-azabicyclo [2.2.2] octanes, 225 Benzimidazoles, 385-389, 470, 475, 485 N-Arylamidinobenzomorphans, 177 Benzitramide, 312 5-Arylazabicyclooctanes, 223 Benzodiazepines, 438 6-Arylbenzomorphans, 160, 162, 184 'Y-Benzomorphan, 166 5-Arylmorphans, 18, 144,215,225,279,431, Benzomorphans, 117, 146, 153,372 481,483 acetylcholine analogs, 186, 191 bridged, 219 amidinium analog, 173 Index 505
Benzomorphans (Cant.) I-Bromocodeine, 32 amino acid derivatives, 180 14-Bromocodeinone, 24, 83 antagonists, 420, 422 (+ )-7-Bromodihydrocodeinone dimethyl ketal, aromatic substitution, 181 413 N-bromoalkyl, 181 N-2-Bromoethylnormetazocine, 449 13C nmr, 204 I-Bromomorphine, 32 4,4-disubstituted, 194 2-Bromopropionyl resin, 342 N-furfuryl, 178 Buprenorphine, 73, 128, 189,406,410-411 'H nmr, 196 pKa' 461 molecular geometry, 205 16,17-Butanomorphinans, 462 ORD/CD, 204, 207 Butorphanol, 110, 132-133, 141, 184,406, parent ring, 183 411,415,418-419,423,427 peptides, 372 antagonist actions, 414 ll-position configuration, 190 19(R)-Butorvinol, 487 quaternary salts, 177 6-t-Butylbenzomorphans, 184 rearrangement products, 194 receptor multiplicity, 353 CAM,416 ring variants, 196 CHAPS, 447, 448 specific receptor sites, 359 CNA,449 spectroscopy, 196 /3-CNA, 450, 451 structure-activity-relationships, 205 /3-COA,450 I-substituted, 190 COAM,416 2-substituted, 191 Capsaicin, 6 4-substituted, 193 N-Carbamoylbenzomorphans, 177 5-substituted, 193 Carboxypeptidase, 337 6-substituted, 183 stable peptides, 352 ll-substituted, 185 Carboxypeptidase-resistant peptides, 349 N-substituted, 206-207 Carfentanil, 296 substitution on nitrogen, 176 /3-Casomorphin, 357-358 synthesis, 155 Cat nictitating membrane, 408, 416 N-tetrahydrofurfuryl, 57, 179, 208 China White, 288 X-ray studies, 203-205 Chlornaltrexarnine, 61, 356,449 Benzomorphan-I-one, 473 /3-Chlornaltrexamine, 439 Benzoquinone, 70 l-Chlorocodeine, 32 2-Benzylbenzimidazoles, 466 a-Chlorocodide, 37, 39 N-[(2-Benzylmethylamino)propyl] a-Chloromorphide, pharmacology, 40 propionanilide, 322 /3-Chloromorphide, pharmacology, 40 I-Benzylnorpethidine, 230 Chloroxymorphamine (/3-COA), 65 I-Benzyltetrahydroisoquinoline alkaloids, 389 Cholinergic receptors, 454 Binding affinity measurements, 2, 3, 333 Chymotrypsin, 371 tests for dualists, 408 Ciramadol, 396, 433 Biochemical pharmacology of opioids, 5 Circular dichroism (CD) Bivalent ligands, 4,5-epoxymorphinans, 67 application to peptide conformation, 370 Blood-brain barrier, 2 of methadone, isomethadone, 327 Boc-Ieu-acyloxymethylphenylacetic acid, 342 Claison-Eschenmoser reaction, 53 Boc-Ieu-enkephalin-OMPA, 342 Clastic binding, 464, 466 Boc-Ieu-resin, 340, 341 Clinical trials, 3 Bradykinin, 407 Codeine, 9, 22-23, 75, 92, 229, 312, 389 Bremazocine, 177,292,438,448 B/C trans-, 24, 27 [3H] analog, 437, 439, 448 C-ring rearrangements, 37 (-)_[3H] analog, 438 clinical, 11 synthesis, 437 GPI responses, 408 14/3-Bromoacetarnidomorphine,448 interconversions, 23 506 Index
Codeine (Cont.) DTLET,434 metabolic O-demethylation, 90 Darvon, 312 metabolism, 26, 87 N-Dealkylation, 233, 467 oxidation, 26 Decahydroisoquinolines, 246 phannacology, II ,6.16.17_Dehydroheroinium chloride, 68 synthesis, 14, 22 7,8-Dehydronaltrexone, 430 ( + )-Codeine, 28 15-Dehydrononnorphine, 90 ( - )-Codeine Delta (6) receptors, 354 binding value, 488 adenylate cyclase, 489 biomimetic synthesis, 16 interaction with wreceptors, 490 synthesis, 18 Demerol, 229 Codeine-7,8-oxide, 49, 90 Demethoxydeoxodihydrosinomenine, 144 Codeine derivatives, IH nmr, 84 6-Demethoxythebaine, 75 Codeinone, 22, 24-25 N-Demethylation, 177, 467 Michael-type additions, 52 N-Demethylation procedures, 30 reaction with lithium dialky !cuprates, 50 (±)-3-Deoxy-7,8-dihydromorphine, 125 Codorphone, 52 3-Deoxydihydromorphinan-6-one, 123 Computer graphics, 375, 459, 471, 484, 487, Deoxydihydrothebaine, 126 494,496 I-Deoxyethylketazocine, 435 4-Cyanobenzomorphan, 193 3-Deoxymorphinans, 430 16-Cyanoheroin, 68 3-Deoxymorphines, 430 Cyclazocine, 117, 176-178, 182,413,421, 6-Deoxyorvinols, 80 423,425-426,434 6-Deoxythevinols, 80 GPI responses, 408 Dependence, 4 clinical potency, 407 Dennorphin, 346, 363 pKa' 461 Hyp6-Dennorphin, 363 sodium index, 335 Phel-Dennorphin, 363 (-)-Cyclazocine, binding value, 488 N-Desmethylmethadol,304 Cyclizine, 307 a-( - )-N-Desmethylmethadol, 325 Cyclocodeinone, 138 N-Desmethylmethadone, 304 7,14-Cyclodihydrocodeinone, 49 3-Desmethylprodine, 252, 255 Cyclohexanes, 390 N-Desmethylpropoxyphene, 312 N-Cyclopropylmethyl (CPM), 424 Desomorphine, 37 N-Cyclopropylmethyletorphine, 80 Dextromethorphan, 114, 146 Cyclorphan, 141,417,420,424 Dextromoramide, 297, 307-308, 318-319, 327, clinical potency, 407 459, 470, 479 Cyprenorphine, 409 human phannacology, 308 Cysteine, 451 pKa' 461 Dextropropoxyphene, 312, 319, 327 D' Amour Smith test, 449 Dextrorphan, 119, 145, 333, 454, 489 DADL, 288, 292, 305, 344, 347-348, 356- (+ )-Dextrorphan, binding value, 488 358,371,374,388,435,436,439,451, Dezocine, 397-398, 433 491-492 Diacetylmorphine (heroin), 11 eH]DADL, 448 Diallylnonnorphinan, 335 DAGO, 288, 292, 305, 349, 356, 436, 439, Diaminocyclohexanes, 438 448 Diamorphine (heroin), II DALAMID, 344, 356 pKa' 461 eH]DALAMID, 388, 447-448 Diampromide, 239, 287, 307, 311, 320,475 DALECK,454 configuration, 320 DAMME,350 (+ )-Diampromide, 319 DCCI,341 Diampromide analogs-analgesia, 321 DSLT, 356, 358, 448 Diazatwistane, pethidine analog, 246 Index 507
Dicodid,37 6-Dimethylamino-4,4-diphenylheptan-3-one, Diconal, 307 303 Dicyclohexylcarbodiimide (DCCI), 338 11,11-Dimethylbenzomorphan, 177 Diels-Alder adducts of thebaine, 69 3,11(j-Dimethylbenzomorphan, 164 Digitonin, 448 3,6-Dimethylbenzomorphan, 155, 160 Dihydro-(j-FNA,451 6,II-Dimethylbenzomorphan, 166 Dihydrocodeine, 37 4,6-Dimethylbenzomorphans, 193 Dihydrocodeinone, 25, 37, 412 5,6-Dimethylbenzomorphans, 193 Hofmann degradation, 83 cis-6, II-Dimethylbenzomorphans, antagonists, ORO and CD spectra, 86 425 Schmidt rearrangement, 83 3,17-Dimethylmorphinan phosphate conversion to 7a-alkyldihydrocodeinones, 41 (Dimemorfan), 121 enol acetate, 126 6,8-Dioxamorphlnans, 420 reaction with formaldehyde, 43 Dioxobenzomorphans, 190 (+ )-Dihydrocodeinone, 28, 117 Diphenoxylate, 312 (-)-Dihydrocodeinone, 32 3,3-Diphenyl-N,N-
Endo-etheno-tetrahydrooripavines, 26, 50, 75, Enkephalins (Cont.) 77 prohormone precursors, 364 Endo-ethenotetrahydrothebaines, 70, 487 radioimmuno assay, 362 antagonists, 409 role of Tyrl, 343 IH nmr, 85 SAR,342 ozonolysis, 75 spectrofluorimetry, 370 Endopeptidases, 343 synthesis, 338 ~u-Endorphin, 360 [3H]Enkephalins, 492 ~c-Endorphin, 361 Ephedrine, 407 ~h-Endorphin, 359,490 4,5-Epoxymorphinan oxetanes, 44, 60 ~-Endorphin, 338, 351-353, 359-364, 492 4,5-Epoxymorphinan oxiranes, 40 N-terminal acetyl, 360 4,5-Epoxymorphinans bovine, 354 antagonists, 409 human, 360 aromatic ring substitution, 32 porcine, 360 B/C trans, 27 a-Endorphin, porcine, 354 furano and pyrrolo, 43 Endorphins, 333, 337-338, 359, 375,445,459, geometric modifications, 27 467,478 mass spectra, 86 CD,370 metabolic N-demethylation, 90 SARs, 360 metabolism, 87 pituitary, 362 I3C nmr, 85 prohormone precursors, 364 IH nmr, 84 salmon, 360 RD and CD spectra, 86 synthesis, 338 receptor probes, 61 Enkephalin, 338, 345, 467 stereochemistry, 27 pig brain, 335 structure activity relations, 91 Enkephalinamide, 369,486 substituted on nitrogen, 29 Enkephalinase, 337, 363 N-substituted, 93 Enkephalins, 3, 295, 333, 335, 337, 339, 343, 5-substituted, 35, 92 359, 364, 445-447, 459-460, 476, 478, 6-substituted, 37, 92 486-487 7-substituted, 40, 92 affinity labels, 348 8-substituted, 50, 92 alkene analogs, 346, 371 14-substituted, 54, 92 N-allyl analogs, 434 14~-substituted, 60 benzomorphan analogs, 372 6,20-Epoxyorvinols, 81 bivalent ligands, 68 6,20-Epoxythevinols, 81 bridged Pen5 analogs, 357 Ethoheptazine, 242, 244 cyclic analogs, 372 2-thienyl analog, 241 I3C nmr, 368 Ethylcodeine, 33 CD,370 I-Ethylcodeine, 32 enzymatic degradation, 336 Ethylketazocine, 67, 288, 305, 356-357, 361, Gly2 variants, 343 435-436,451 Gil variants, 345 antagonist actions, 414 in vitrolvivo activities, 336 [3H]Ethylketocyciazocine, 435 isolation and characterization, 335 N-Ethylmaleimide, 356 Leu5/Met5 variants, 347 Ethylmorphine, 26 parenterally and systemically active analogs, N-Ethylnormorphine, 427 349 14~-Ethylmorphinone, 61 pharmacokinetics, 337 a-3-Ethylpiperidines, 260 physical dependence and tolerance, 338 Etonitazene, 387-389,453,459-461,477, Phe4 variants, 346 479 Pro5 analogs, 347 pK., 461 Index 509
Etorphine (Immobilon), 71, 80, 93,128,355- GTP, 492 356,375,388,411,489 GTPase, 489 N-allyl, 410 Gaddum drug ratio, 406 sodium index, 335 Galt's proposal, 481 X-ray study, 87 Goldstein's stereospecific binding technique, (-)-Etorphine, binding value, 488 445 eHjEtorphine, 346, 356, 372, 447, 463, 484, Grewe synthesis, 16, 18, 132, 185, 193 490,492 of benzomorphans, 165 Etoxeridine, 235 of morphinans, 106 Guinea pig ileum (GPI) test, 3,407 FAO, 453, 454 Guinea pig ileum preparation, 2 FIT, 288,453-454, 492 i3-FNA, 413, 450-452, 457, 465 Halocodides, 53 a-FNA,451 14-Halocodides, 39 i3-FOA, 450-451, 457 i3-Halocodides, 39 FX-33-824, 338, 346, 350, 352, 353, 355, 359, Halomorphides, 53 487 a-Halomorphides, 53-54 synthesis, 340, 341 i3-Halomorphides, 53-54 Fast-atom bombardment MS, 335 Haloperidol, 287 Fentanyl, 241, 281, 287, 289, 293, 295-297, Hasubanan, 144 393,408,459,466,468,474,477,479, Hasubanonine, 9, 83, 144 485, 494, 496 Heptalgin, 306 affinity labels (photo), 299, 453 Heroin, 23, 68, 304, 338, 469, 489 analogs, 452 human metabolism, 90 binding studies, 288 metabolism, 87 clinical use, 287 pKa' 461 conformation, 290, 298 pharmacology, 11 cyclic analogs, 298 receptor binding, 27 'H nmr, 290, 298 in vivo hydrolysis, 89 metabolism, 288 (+ )-Heroin, 28 1-methyl-3-allyl, 292 Heroin-7,8-oxide, 49 pharmacokinetics, 288 Heterocodeine, 39 phenolic analogs, 295 N-Hexylnorpethidine, 239 pka, 295 Histamine, 6 3-propyl, 291 Histaminic receptors, 454 SARs, 288 liot-plate assay, 2 3-substituted analogs, 290 Human tests, 3 4-substituted analogs, 296 Hybromet, 453 synthesis, 288, 292 Hydrocodone, 33, 37 tropane-based analogs, 294 Hydrogen-transfer interactions, 465 Fluorescence microscopy, 447 ( - )-Hydromorphine, binding value, 488 1-Fluorocodeine, 32 Hydromorphone, 37 Fluorophen, 447 N-methyl, 480 Fortral, 176, 421 pKa' 461 Fries and Portoghese proposal, 482 14-Hydroxy-3-methoxy-N-methylmorphinans, Funaltrexamine (i3-FNA), 65 133 Fuoxymorphamine (i3-FOA), 65 8-Hydroxy-6,11-dimethylbenzomorphans, 181 Furethidine, 235 (+ )-3-Hydroxy-N-allyJmorphinan, binding 2-Furfurylbenzomorphans, 427 value, 488 3-(3-Furylmethyl)-6,11-diethyl-8- 3-Hydroxy-N-methylisomorphinan, 146 hydroxybenzomorphan, 353 2-Hydroxy-N-methylmorphinan, 125 4-(2-Furyl)piperidine, 469 (-)-4-Hydroxy-N-methylmorphinan-6-one, 146 510 Index
14-Hydroxyazidomorphine, 56 Isomorphinan-6-one, 128 11-Hydroxybenzomorphans, 185 Isomorphinans, 113, 136, 146,417,473 l1/3-Hydroxybenzomorphans, 141 a-Isomorphine, 27, 37 8-Hydroxybenzomorphans, 181 Isomorphines, 7-substituted, 47 (±)-2-Hydroxycodeine, 33 Isoneopine, 28 14-Hydroxycodeinone, 39, 153,415 Isoprodines, 245 esters, 59 14-Hydroxydihydrocodeines, 59 Jetrium, 307-308 14-Hydroxydihydrocodeinone, 412 Kappa (K) agonists, 434 from thebaine, 54 dynorphins, 361 14-Hydroxydihydromorphines, 59 prototype agonist (ketazocine), 423, 434 14-Hydroxydihydromorphinone, 54 Ketazocine, 413, 420, 434-435 14-Hydroxydihydromorphinone hydrazones, 57 antagonist actions, 414 14-Hydroxyisomorphinans, 147 Ketobemidone, 237-239, 241, 355, 431, 469 14-Hydroxymorphinan-6-one, 125 N-allyl, 474 (± )-1-Hydroxymorphinan-6-ones, 124 pKa, 461 (-)-3-Hydroxymorphinans, 118 Ketocyclazocine, 206, 353, 423 1-Hydroxymorphinans, 125 Keyhole limpet hemocyanin, 446 14-Hydroxymorphinans, 132-133, 147,427 Kolb's proposal, 480 N-substituted, 426 Kreusigia multiflora, 83 3-Hydroxymorphinans, 119 ( + )-Kreysiginine, 83 4-Hydroxymorphinans, 123 Kyotorphin, 363 14-Hydroxymorphine derivatives, 412 N-Hydroxynormorphine, 90 LPT,359 14-Hydroxynormorphinone, 413 /3-LPT, 360-362 5-(3-Hydroxyphenyl)-2-methylmorphan, 217 LY 150720,277 (-)-5-(3-Hydroxyphenyl)-2-methylmorphan, x• Laudanosine, 9 ray, 218 Leptanol, 287 4-m-Hydroxyphenyl-4-alkylpiperidines, Leritine, 232 pharmacology, 277 Lethidrone, 405 Leu-enkephalin, 336, 341-342, 346, 349, 353- Immobilon, 71, 410 354, 356, 361-362, 370-371, 374, 434, Immunofluorescent mapping, 446 439,446,454,490-492 Imodium, 312 conformation, 367 Indenotetrahydropyridines, 194 pharmacology, 336 Insulin receptor, 495 X-ray diffraction, 364 Ionization constants of opioid ligands, 460 [3HjLeu-enkephalin, 353-355, 371 Isobutorphanol,419-420 Leu-enkephalin-OMe, 372 Isocodeine, 27, 37, 75 D-Ala2-Leu5-enkephalin-NAP-EDA, 454 B/C trans-, 24 [Leu5j-/3wendorphin, 360 7-substituted, 47 Leucine enkephalin, 50, 336 Isocodeine derivatives, IH nmr, 84 Levallorphan, 72, 115,389,413,416-417 Isocyclorphan, 417, 420 clinical potency, 407 Isofentanyl, 295 GPI responses, 408 Isolevorphanol, sulfonium analogs, 465 pKa' 461 a-Isomethadol, 309 sodium index, 335 Isomethadols, 309 ( - )-Levallorphan, binding value, 488 Isomethadone, 305, 307, 309 Levophenacylmorphan, 118 configuration, 315, 318 Levorphanol, 26, 113, 119, 145, 180,204, pKa' 461 333-334,355,407,416,448,450,454, X-ray crystallography, 327 464,469 ( - )-Isomethadone, 318, 327 ORD and CD studies, 116 Index 511
Levorphanol (Cont.) [O-Met2, Thz5]-enkephalinamide, 352 absolute configuration, 115 Met5-ol-enkephalin, 350 methiodide, 463 Metabolism of analgesics, 5 N03 analog, 465 Metagonists, 456 pKa, 461 Metamorphinans, 143 sodium index, 335 Metaphenin, 9 sulfonium analogs, 465 Metaphenine, 145 ( - )-Levorphanol, binding value, 488 Metathebainone, 143 Ligand-receptor association, 460 Metazocine, 177, 193,203,486 Ligand-receptor interactions, computational ORO, 204 approach, 493 sodium index, 335 {3-Lipoprotein, 354 a-Metazocine, 280, 282, 353 {3-Lipotropin, 60-65, 359, 364, 372 analogs, 424 Literature of opioids, 6 {3-Metazocine, 473 Lock-and-key model, 459 a-( - )-Methadol, 324 Lofentanil, 296-297 fJ-( - )-Methadol, 324 Lomotil, 312 a-Methadol, 309, 320, 327 Lorphan, 115 pKa' 461 3,4-Lutidine, 166 ( - )-a-Methadol, 322 configuration, 323 cyanobromide, 323 MMMS, 494 N-CPM,31O MR 2266, 435-436, 438 N-allyl, 310 MRZ 2549, 437 Methadols, 309, 324, 470 Meperidine, 229 MHP, 323 (±)-Meperidine, binding value, 488 X-ray crystallography, 327 Meperidinic acid, 237 Methadone, 160,303,305,309,317,334,355, Meprobamate, 407 388,407,445,459-460,467,470,474- Meptazinol, 282 475,479,489 Meptid,282 absolute configurational studies, 316 (OL)-(3-Mercapto-2-benzylpropanoyl)glycine, activity of antipodal pairs, 314 337 in addict rehabilitation, 304 Merck Molecular Modeling System, 494 p-agonist, 305 Met-enkephalin, 336-338, 343-346, 348-351, t-amide analogs, 308 353-356,358-364,369-372,415,434, analogs, 468 446, 487-492 basic oil, 305 big metenkephalins, 362 binding values of antipodes, 488 conformation, 367-368 clinical use, 303 'H nmr, 365 conformation, 321 pharmacology, 336 ethyl ketone variants, 308 synthesis, 339-340 human pharmacology, 303 Met(O)-enkephalin, 362 metabolism, 304, 313 Arg6-Met-enkaphalin, 362 5-methyl analog, 326 [Arg6, PheMet]-enkephalin, 362 6-methyl analog, 317 Met-enkephalin analogs, analgesia, 351 nitrile precursor, 316 Met-enkephalin-Arg6, 362 N-oxide, 305 Met-enkephalin-Arg6-Phe7, 362 N-substituted analogs, 306 Met-enkephalin-Lys6, 362 ORO/C~, 327 Met-enkephalinamide, 346-348, 434 physical dependence, 304 [O-Met2, Pro5]-enkephalin, l3C nmr, 369 pKa' 461 [D-Met2, Pro5]-enkephalinamide, 346, 352- quantum chemical studies, 327 353, 355, 370 reduction products, 309 512 Index
Methadone (Cont.) Metopon, 41, 92 resolution of precursor, 314 synthesis, 20 SAR,306 synthesis and pharmacology, 35 sodium index, 335 Molecular orbital calculations, 461 synthesis, 305 3-Monoacetylmorphine, 27 X-ray crystallography, 325 6-Monoacetylmorphine, 11, 89 a-Methadyl acetate, 304, 327 Morphans,215 Methionine enkephalin, 180, 193, 336 Morpheridine, 235 Methopholine, 390 Morphiceptin, 357-358 Metho salts of opioid ligands, 461, 463 Morphinan 3-Methoxy-N-chloromorphinan, 143 antagonists, 416 . 7-Methoxycodeine,49 photoaffinity labeling reagent, 119 (±)-Methoxyhasubanan, 144 ring variants, 137 14-Methoxymorphinan-6-ones, 135 (+ )-Morphinan, 115 2-Methoxymorphine, 90 (±)-Morphinan, cyc\opentane C-ring analogs, 5-(3-Methoxyphenyl)-2-methylmorphan-9-one, 138 219 Morphinan-6-ones, 119, 121, 128, 146,418,469 Iia-Methylbenzomorphan, 185 7-substituted, 126 lliJ-Methylbenzomorphan, 185 8-substituted, 130 2-Methylbenzomorphan, 172 reaction with formaldehyde, 129 3-Methylbenzomorphan, 162 Morphinans, 105, 181 3-Methylbenzomorphan-I-one, 172 7-substituted, 126 N-Methylbenzomorphans, 428 8-substituted, 130 (-)-l-Methyldihydrocodeine, 32 IO-substituted, 132 7iJ-Methyldihydrothebaine-, 43, 126 D-ring expanded, 141 5-Methyldihydrothebainone, 126 N-substituted, 147 7-Methyldihydrothebainone, 126 X-ray, 117,462 3-Methylfentanyl, 290 aromatic ring substitution, 119 a-Methylfentanyl, 288 stereochemistry, 113 cis-3-Methylfentanyl, 296, 299 structure-activity relationships, 146 cis-3-Methylfentanyl derivatives, 297 substitution on nitrogen, 117 N-Methylisomorphinan, 112 synthesis, 105 iJ-3-Methylketobemidone, 276, 432 B/C trans, 28 6-Methylmethadone,317 (-)-Morphinans, CPM derivatives, 117 5-Methylmethadone diastereoisomers, 326 Morphine, 2, 9, 22-23, 26, 113, 117, 145, 181, 5-Methylmethadones, 'H nmr, 326 229, 277-278, 303, 338, 345-346, 349- 2-Methylmorphan, 226 351, 353-355, 358, 360, 363, 375-376, 7a-Methylmorphinan-6-one, 126 388-389,405,410,416,420,429,457, I-Methylmorphine, 32 469, 478, 489 N-Methylmorphine, 463 acyl derivatives, 23 N-Methylmorpholine, 340 antagonist actions, 414 l-Methyl-4-pheny 1-4-piperidinol B/C Trans, 27, 92 esters, 243 \3C nmr studies, 27 from a-methylstyrene, 268 C-ring rearrangements, 37 propionanilide analogs, 238 CPM derivatives, 117 (-)-iJ-2-Methyl-4-phenyl-4-piperidinol, X-ray, clinical, 11,407 273 GPI responses, 408 2-Methyl-5-phenylmorphan, 215 interconversions, 22-23 ll-iJ-Methyl-6-phenylbenzomorphan, 428 metabolism, 87 5-Methylprodine, 273 ND3 analog, 464 Metkephamid, 345, 346, 350 N-oxides, 32 Index 513
Morphine (Cont.) Nalmexone, 55, 414 pK.,461 Nalorphine, 1-2,5,30,37,55,72-73, 117, phannacology, 10 176,277-278,334,398,405-406,409- quaternary salts, 32 411,413,416-417,421-422,429-430, ring variants, 82 451,457,460,463,471,489 sodium index, 335 animal phannacology, 405 stereochemistry, 10, 27 antagonist actions, 414 synthesis, 14, 16, 20, 136 binding value, 88 undesirable actions, 4 clinical potency, 407 (±)-Morphine, 112, 132 GPI responses, 408 synthesis, 19 human phannacology, 31 (+ )-Morphine, 10, 28, 42 K-agonist evidence, 413 (-)-Morphine, 92, 471 metabolism, 87 binding value, 488 N-methyl analogs, 463 IH nmr, 84 pK.,461 ORO and CO spectra, 86 sodium index, 335 synthesis, 18 (-)-Nalorphine, binding value, 488 X-ray studies, 86 relief of pain in humans, 406 [3H]Morphine, 388 Nalorphine-6-glucuronide, 88 Morphine-3-0-alkyl analogs, 26 Nalorphine-6-sulfate, 88 Morphine-3-glucuronide, 87 Naloxazone, 56, 373 Morphine-3,6-diglucuronide, 87 Naloxone, 1,5,25,55,61,277,334-335,350, Morphine-6-glucuronide, 27,87,91 352-353, 355, 360-361, 363, 374-375, Morphine-7,8-oxide, 49 377,393,400,406,409,412-415,418, Morphine-N-oxide, 68, 90 426,429,435,438,450-451,457,460, Morphine N-oxide 3-glucuronide, 90 463,480,489 Morphine sulfate 6-methylene, 38 natural abundance I3C nmr, 85 GPI responses, 408 solid I3C nmr, 85 N-Methylquaternary salts, 58 Morphine-3-sulfate, 87 (-)-Naloxone, binding value, 488 Morphine-6-sulfate, 27, 87 clinical potency, 407 Morphine-nalorphine pairs, 13C nmr, 86 effect on pain thresholds, 376 Morphine poisoning, 406 hydrazone derivatives, 415 Mouse hot-plate (MHP) assay, 2 metabolism, 87, 91 Mouse vas deferens (MVO) test, 3, 333 pK.,461 Mouse vas deferens preparation, 2 pain perception, 376 Mr1353,437 quaternary salts, 32 Mr2033,437 sodium index, 335 Mr2184,437 (+)-Naloxone, 29, 57, 409, 413 Mr2266,353 [,H]Naloxone, 254, 334-335, 353-355, 357, Multiple receptor concept, 455 360,363,371-374, 391,413,450,452, Multiple uptake modes, 475 488 (+ )-Muscarine, 324 Naltrexamine, 415, 451 (-)-Muscarone, 324 a-Naltrexamine, 450 P-Naltrexamine, 357,439 NAM,416 affinity labels, 449 NIH irreversible ligands, 453 bivalent ligands, 67, 357 NOAM,416 Naltrexazone, 56 Nalbuphine, 55, 406, 414 Naltrexone, 55, 61, 353,406,409,414-415, antagonist actions, 414 429-430,450,457,480,489 Nalmefene, 415 10-keto, 436 514 Index
Naltrexone (Cont.) Normethadol, 309 6-amino,449 MHP, 323 hydrazone derivatives, 415 Normethadone, 305, 307, 309, 312 metabolism, 87, 91 pKa, 461 6-methylene, 38 Normetopon, 35 N-methylquaternary salts, 58 Normorphine, 29, 89-91, 310, 335-336, 338, pKa, 461 348-349,354-355,361,415,429,435 quaternary salts, 32 antagonist actions, 414 [3H]Naltrexone, 452 N-CPM,31 Narcan, 412 standard in in vitro tests, 335 Narceine, 9 Normorphine-3-glucuronide, 90 Narcotic antagonists, 7 Noroxycodone, 56 Narcotics, 4, 7 Noroxymorphone, 56, 412 Narcotine, 9 Norpethidine, 230-231, 310, 312 a-Narcotine, 389 dibenzocycloheptene analog, 236 Narphen, 177 Mannich bases, 234 a-Neoendorphin, 361, 362 N-allyl, 431 (3-Neoendorphin, 361 N-substituted, 231 Neopinone, 24 Norprodine, N-allyl, 431 Nepenthone, 73 R-( - )-Norrecticuline, 16 Neuroblastomaglioma hybrid NO 108-15,447, Nortilidine, 394 489 Noscapine, 389 site of a-receptors, 489 Nubain, 414 test for antagonists, 409 Numorphan, 54 Nicotinic receptor, 495 Nilsen test, 407 pA2 opioid antagonists, 406 Nisentil, 253 morphine derivatives, 409 I-Nitrocodeine, 33 naloxone vs. agonists and dualists, 413, 451 14-(3-Nitrocodeinone, 448 Operidine, 234 Nitrogen lone-pair effects, 31 Opiate, N-mustards, 61, 65 Nitrogen lone-pair orbital orientation, 462, Opioid binding assays, 408 465 Opioid-binding sites, affinity assay, 254 2-Nitromorphinan, 119 Opioid ligands 3-Nitromorphinan, 119 aromatic features, 467 I-Nitromorphine, 33 oxygen functions, 468 N-Nitrosonormeperidinic acid, 234 role of N-substituent, 466 [Nle5]-enkephalin, 349 stereochemical features, 470 [D-Nle2,L-NleS5]-enkephalin, 368 Opioid peptides, 333 [D-Nle2-Leu5]-enkephalinamide, 374 affinity labels, 61 Noradrenaline, 6 13C nmr, 365 Norcodeine, 89 conformationally restrained analogs, 371 Norfentanyl, 288 conformational studies, 364 N-substituted, 289 cyclic analogs, 373 Norheroin, 27 isolation, 447 Norketobemidones, N-substituted, 239 'H nmr, 365 Normetazocine quantum mechanical calculations, 370 N-(-y-cyanopropyl)-, 118 role in tolerance and dependence, 376 N-(2-bromoethyl),232 SARs, 342-343 N-fluoralkyl, 180 Opioid receptors N-substituted, 426 E-receptors, 356 (±)-Normetazocine, N-«(3-Cyanoethyl), 118 localization, 446 Index 515
Opioid receptors (Cont.) Paracetamol,312 "lock and key" model, 459 Paracodin, 37 models, 471 Parenterally active peptides. 349 /1 and 0 of Kosterlitz, 354 D-Penlcillamine ({3, (3-dimethylcysteine), 373
/1, K, and (I of Martin, 353 Pentazocine, 72,117,172,177-178,203,277- multiplicity, 93, 353 278,282,334,397,399,406,413,418, scenarios, 454 421,424-425,427,430,436 selective protection, 355 clinical potency, 407 special aspects of 0, 489 GPI responses, 408 subsites (T and P), 478 pKa,461 zipper mechanism, 459 sodium index, 335 Opium, I, 389 synthesis and pharmacology, 176 Oripavine-7-methanols, 188 (±)-Pentazocine, binding value, 488 Oripavines, 23, 473 N-Pentylnorpethidine, 239 N-CPM,467 Peptide E, 362 Orvinans, 77 Peptide bivalent ligands, 357 Orvinols, 77, 79-80 Pethidine, 2, 229, 253, 275, 345, 394, 417, Orvinones, 77 420,445,459,469,480,485 8-0xaisomorphinans, 140-141 (3-analogs, 245 8-0xamorphinans, 140-141 binding studies, 231, 254 Oxilorphan, 132-133,409,418,421,423,480 C-4 variants, 236 14-{3-thiol analog, 419 clinical use, 229 6-allyl-11-0xobenzomorphan, 422 conformational energy calculations, 275 1-0xobenzomorphans, 190, 195 conformationally restrained analogs, 245 11-0xobenzomorphans, 156, 185, 195 distribution, 231, 253 6-0xomorphinan, 110 impurities and pharmacopoeial specifications, Oxomorphinans, 186 230 Oxycodone, metabolism, 91 metabolism, 230, 253 ( - )-Oxycodone, binding value, 488 N-substituted analogs, 231
Oxylorphan, 110 pKa ,461 Oxymorphamine,68 sodium index, 335 {3-0xymorphamine, bivalent ligands, 67 4(2-thienyl) analog, 241 Oxymorphazone, 56, 415 tolerance, 229 Oxymorphine, pKa, 461 tritiated analog, 233 Oxymorphone, 54, 134, 423, 426, 450, 480 Pethidine reversed esters, 237 6-amino, 449 N-allyl analogs, 239 6-azido, 56 antipodal forms of 3-R analogs, 237 pKa,461 4-aryl analogs, 240 sodium index, 335 2,3-dimethyl analogs, 259, 262, 265 Oxymorphone-naloxone, 430 2,6-dimethyl analogs, 261, 264 Oxymorphone-naloxone pairs, I3C nmr, 86 3,5-dimethyl analogs, 260, 264 3,3-dimethyl analogs, 274 PCP, 393-394 4-(2-furyl) analog, 242 PET, 477 5- and 7-membered ring analogs, 244 PETT,447 2-methyl analogs, 261,265 PGEI,489 nmr (,H, 13C) evidence of stereochemistry, PGEI-stimulated cAMP levels, 409 270 Palfium, 307-308 phenolic analogs, 241 Papaver bracteatum, 23-25 piperidine ring methylated analogs, 256 Papaver somniferum, 9, 22-23, 25 QSAR study, 243 Papaverine, 9, 389 resolutions, 269 516 Index
Pethidine reversed esters (Cont.) Physeptone, 303 SARs,273 Physical dependence, abstinence phenomena, 4 stereochemistry, 257, 266, 269 Picenadrol (L YI50720), 277 synthesis, 237, 267 Pilocarpine, 407 tropane analog, 263 Piminodine, 232, 238 X-ray crystallography, 272 Pipadone, 306 [D-Phe4]-enkephalins, 371 Piperidinols, as benzomorphan precursors, 172 Phenadoxone, 306, 314 4-Piperidinols, 398 (-)-Phenadoxone, 317 4-piperidones, 266 Phenampromide, 311, 320 , 3-ally I, 267 ( - )-Phenampromide, 319 , synthesis, 266 Phenazocine, 73, 176-177,410,420,428,432, Piridolan, 313 447,477,479 Pirinitramide, 313 pKa,461 Piritramide, 313 sodium index, 335 Pituitary gland, source of opioid peptides, 359, Phencyclidine, 392-393 361 I-Phenethylcyclohexan-I-ols, 393 pKa values of opioid ligands, 460 1-Phenethy 1-1,2,3 ,4-tetrahydroisoquinolines, Portoghese-Takemori hypothesis, 457 390 Portoghese pivot model, 226, 476 N-Phenethylnorpethidine, 231, 289 Positron-emission, transaxial tomography, 447 N-Phenethylprodines, 252 Prochirality, 259 Phenomorphan, 118 Pro-enkephalin, 495 Phenoperidine, 234, 238 Pro-opiomelanocortin, 364 Phenoxybenzamine, 355 Prodilidine, 244 4-Phenyl-l-tetralone, 162 Prodine,480 5-Phenyl-2-methylmorphan, 216 a-Prodine, 241, 252-253, 256, 260-261, 269, I-Phenyl-3-azabicyclo[3.3.1]nonanes, 226 272-273, 275 Phenylalaninol, 349 {3-Prodine, 241, 252-253, 255-256, 262-263, II-Methyl-6-phenylbenzomorphans, 482 269, 272-273, 291, 432 6-Phenylbenzomorphans, 184, 207,424 Prodines (a and (3) ORD/CD,204 3-alkyl and 3-allyl analogs, 255 Phenylmorphans, 480, 482 binding affinities, 253 Phenyloripavine,479 confonnational energy calculations, 275 4-Phenylpiperidines, 222, 229, 251, 469, 473, distribution and metabolism, 254 476, 479-480, 483-484 iso analogs, 245 alkyl substituted, 243 nmr CH and I3C), 269 analogs, 243 N-phenethyl analogs, 252 antagonists, 239 pKa,461 azabicyclane analogs, 246 resolution, 269 C-4 oxygen variation, 236 stereochemical SARs, 253 decahydroquinoline analogs, 246 X-ray studies, 252, 269 N-dealkylation, 233 (+ ){3-Prodinol, 273 phenolic, 276 Prodynorphin, 364 quinolizidine analogs, 246 Proenkephalin-A, 364 stereochemical SARs, 253 Profadol, 223, 251, 281-282 4-(N-Phenylpropionamido )piperidines, Promedols, 251, 261, 266, 293 phannacology, 292 synthetic intennediate, 267 Phenylquinone, 407 a-Promedol, 255-256, 262, 273, 482 Pheol,349 {3-Promedol, 265 Pholcodine, 26 'Y-Promedol, 253, 260, 270, 272-273, 482 PhosphOlipase A, 447 'Y-Promedol alcohol, 'H nmr, 270 Photoaffinity labels, 454 Promedol alcohols, I3C nmr, 271 Index 517
Prometaphenine, 145 Receptor models, 471 Propiram, 311 Beckett and Casy, 471 Propoxyphene, 311, 319 Barnard and Demoliou-Mason, 492 absolute configuration, 318 Collier and Roy, 481 cyclic analog, 312 Galt, 481 dextro isomer, 312 Humblet and Marshall, 484 pyrrolidino analogs, 312 Portoghese, 475, 482 (±)-Propoxyphene, binding value, 488 Snyder, 477 a-3-Propylpiperidines, 260 Receptor multiplicity, 353 Protometaphenine, 9 Receptor scenarios, 454 Psychotomimetic reactions, 5 Receptor solubization techniques, 447 Puromycin, 337 Respiratory depression, 4, 5, 495 (+ )-Reticuline, 14 Revivon,410 Quantum chemical calculations, 493 Rimorphin,361 Quantum pharmacological studies, 494 Romilar, 114 Quinolizidines, 246 Route of administration, 2 Rouden-Smith test, 335 R-875, 308 R951,234 Rabbit vas deferens, sensitivity to K-agonists, SARs,458 361,414,435 SKF-10047,420-421 Racemorphan, 5-membered ring D analog, 462 Salutaridine, 14 Rat tail-flick (RTF) assay, 2 Schild's pA2 value, 406, 409, 413, 451 Rat tail withdrawal (RTW) assay, 2 Serotonin (5-HT), 6 Rat vas deferens, low sensitivity to K agonists, Side effects of opioids, 3 361 Sinomenine, 9, 115, 144,207 Receptors, multiple, 93 (-)-Sinomenine, 28, 57 o-Receptors, 6, 58, 68, 208, 231,288, 328, Sinomenium acutum, 144 344-345, 347-349, 354-359, 370-371, Snyder, receptor hypothesis, 477 373-374,388,435,439,448,450,453- Sodium index, 334, 411, 446 455,458,489-492 Solid-phase peptide synthesis, 338, 341 J.I-Receptors, 30, 58, 68, 208, 231, 288, 292, 360 328, 344-345, 347-349, 352-359, 368, Solubilization agents, 371, 373-374, 388,429,435-436,438- CHAPS, 447 439,448,450-455,457-458,471,487, digitonin, 448 489-492,495 Triton X-100, 448 aromatic binding sites, 221 Zwittergent, 448 J.I-Receptor agonists, 275 Stadol,418 J.Io-Receptors, 452 Stephaniajaponica, 83, 144 I'M-Receptors, 452 Stereospecific binding, 333 K-Receptors, 30, 66, 68, 177, 206, 231, 353- Stevens rearrangement, synthesis of 354,356-357,359,361,374,413,435- benzomorphans, 170 438, 448, 450-452, 455 Straub tails, antagonist test, 409 a-Receptors, 30, 455 Structure-activity relationships, opioid ligands, p-Receptor subsites, 457 458 1'1 + J.I2-Receptor, 492 Sublimaze, 287 01 + orReceptor, 492 Substance P(SP), 6 J.I-o-Receptors, 458 14-Substituted normorphines, N-CPM interactions of, 490 antagonists, 429 K + o-Receptors, 492 N-Substituted-4-phenyl-4- Receptor isolation, 447 propionoxypiperidines, 238 518 Index
Sufentanyl, 296, 297 3,4,6-Trimethylbenzomorphan, 166, 168 chemoaffinity functionalized, 299 Trioxobenzomorphans, 190 photoaffinity functionalized, 299 Tris-HCl, 492 Sufentanyl-02 anesthesia, 296 Tropanes, 3-arylpiperidine analogs, 432 Synduphalin, 349 Trypsin, 448 D-Tyr'-Met-enkephalin, 486 Talwin, 421 [3H-Tyr]Leu-enkephalin, 362 Temgesic, 73,410 Tes-KOH, 492 U50488,395,438,448 Tetrahydrofuranobenzomorphans, 140 antagonist actions, 414 N-TetrahydrofurfUlyl benzomorphans, 427 Upjohn's cyclohexanol, 391 Tetrahydroisoquinolines, 389 I-Tetralone, 1l0, 155, 183-185, 190 Valoran, 394 2-Tetralone, 110, 155, 185, 191, 194, 398 Van der Waals bonds, 467, 472 Thalamontal, 287 Viminol, 400-401, 433 Thebaine, 9, 22, 24, 28, 121,207,412,430 configuration, 400 addition of dinitrogen tetroxide, 60 Volazocine, 182 addition of nitrosobenzene, 60 addition products, 81 addition products with dienophiles, 70 Win 44,441-3 (K-antagonist), 439 Writhing test, 2 bromination, 24 Writhing test analgesia, 407 conversion to metopon, 35 WY-16225,397 Diels-Alder adducts, 60, 69, 70, 93 \3C nmr, 85 SARs, 79 X-ray crystallography interconversions, 23 a-3-allylprodine, 256 nitration, 60 5-arylmorphans, 218 ozonolysis, 153 3-arylpiperidine and pyrrolidine derivatives, reaction with lithium dimethylcuprate, 126 282 synthesis, 22 benzomorphans, 205 ,8-Thebainone, 113 16,17-butanomorphinans, 462 Themalon, 310 leu-enkephalin, 336 Thevinans, 77 etorphine, 87 Thevinols, 77, 79-80 fentanyl, 298 Thiambutenes, 241, 307, 310, 316, 474 methadone and analogs, 327 configuration, 314 morphine, 27, 86 Thioanisole-trifluoromethanesulfonic acid, 340 prodines (a and ,8), 252 Thiomorphinans, 186 racemorphan, five-membered ring D analog, Thiorphan, 337 462 Ticarda, 307 reversed ester of pethidine, C-metbyl Tifluadon, 438 derivatives, 257, 259, 274 Tilidine, 394 tilidine, 395 p-Tilidine, 395 Upjohn's 4-aryl-4-dimethylamino-4- Tolerance, 4 cyc\ohexanol derivative, 392 Tonazocine, 428 viminol, 400 Trarnadol, 395 Tramol,395 Zactane, 244 N-Trideuteriomethylnormorphine,90 Zenazocine, 428 Trifluadom, 448 Zipper mechanism, 459 Trimeperidine, 253, 261 Zwittergent 3-10,448