The aporphine alkaloids constitute the second-largest group of isoquinoline alkaloids. Nevertheless, only a relatively small number of natural aporphines and their derivatives have been studied from a pharmacological viewpoint. Here we review the pharmacological data available for these compounds as related to their dopaminergic, noradrenergic and serotonergic activities, and also some results pertaining to their effects on ion channels and enzymes.
ShammaM. (1972) Isoquinoline Alkaloids: Chemistry and Pharmacology.Academic Press, New York, 194–228.
2.
BrownGM, HallLH. (1977) The crystal structures, molecular structures, and absolute configurations of the hydrobromides of the aporphine alkaloids leukoxine and isoboldine. Acta Crystallographica, B33, 2051–2057.
WooSH, SunNJ, CassadyJM, SnapkaRM. (1999) Topoisomerase II inhibition by aporphine alkaloids. Biochemical Pharmacology, 57, 1141–1145.
5.
MathiessenA, WrightCRA. (1869) Researches into the chemical constitution of narcotine and of its products of decomposition. Proceedings of the Royal Society, B17, 455–462.
6.
ZhangA, NeumeyerJL, BaldessariniRJ. (2007) Recent progress in development of dopamine receptor subtype-selective agents: potential therapeutics for neurological and psychiatric disorders. Chemical Reviews, 107, 274–302.
7.
ZhangA, ZhangY, BranfmanAR, NeumeyerJL, BaldessariniRJ. (2007) Advances in development of dopaminergic aporphinoids. Journal of Medicinal Chemistry, 50, 171–181.
8.
ErnstEM, SmelikK. (1966) Site of action of dopamine and apomorphine on compulsive gnawing behaviour in rats. Experientia, 22, 837–838.
9.
NeumeyerJL, NeustadtBR, WeinhardtKK. (1970) Aporphines. V. Total synthesis of (plus or minus)-apomorphine. Journal of Pharmaceutical Sciences, 59, 1850–1852.
10.
NeumeyerJL. (1985) Synthesis and structure-activity relationships of aporphines as dopamine receptor agonists and antagonists. In The Chemistry and Biology of Isoquinoline Alkaloids. PhillipsonJD, RobertsMR, ZenkMH (Eds). Springer-Verlag, Berlin, Germany, 146–170.
11.
HenryGW. (1932) Catatonia in animals: experimental studies on the effect of bulbocapnine and other drugs. American Journal of Psychiatry, 88, 757–793.
12.
González-VegasJA, WolstencroftJH. (1971) Antagonism of noradrenaline and dopamine inhibition of brain-stem neurones by bulbocapnine. Journal of Physiology, 214, 16P–17P.
13.
ZetlerG. (1988) Neuroleptic-like, anticonvulsant and antinociceptive effects of apomorphine alkaloids: bulbocapnine, corytuberine, boldine and glaucine. Archives Internationales de Pharmacodynamie et de Thérapie, 296, 255–281.
14.
AsencioM, DelaquerrièreB, CasselsBK, SpeiskyH, ComoyE, ProtaisP. (1999) Biochemical and behavioral effects of boldine and glaucine on dopamine systems. Pharmacology Biochemistry & Behavior, 62, 7–13.
15.
Sobarzo-SánchezEM, ArbaouiJ, ProtaisP, CasselsBK. (2000) Halogenated boldine derivatives with enhanced monoamine receptor selectivity. Journal of Natural Products, 63, 480–484.
16.
LoghinF, ChagraouiA, AsencioM, ComoyE, SpeiskyH, CasselsBK, ProtaisP. (2003) Effects of some antioxidative aporphine derivatives on striatal dopaminergic transmission and on MPTP-induced striatal dopamine depletion in B6CBA mice. European Journal of Pharmaceutical Sciences, 18, 133–140.
17.
AsencioM, Hurtado-GuzmánC, LópezJJ, CasselsBK, ProtaisP, ChagraouiA. (2005) Structure-affinity relationships of halogenated predicentrine and glaucine derivatives at D1 and D2 dopaminergic receptors. Bioorganic & Medicinal Chemistry, 13, 3699–3704.
18.
Dajas-BailadorFA, AsencioM, BonillaC, ScorzaMC, EtcheverryC, Reyes-ParadaM, SilveiraR, ProtaisP, RussellG, CasselsBK, DajasF. (1999) Dopaminergic pharmacology and antioxidant properties of pukateine, a natural product lead for the design of agents increasing dopamine neurotransmission. General Pharmacology, 32, 373–379.
19.
SaumWR, GroatWC. (1972) Antagonism by bulbocapnine of adrenergic inhibition in parasympathetic ganglia in the urinary bladder. Brain Research, 37, 340–344.
20.
IlhanM, LongJP, CannonJG. (1975) Bulbocapnine's ability to antagonize the adrenergic inhibitory action of dopamine and analogs. European Journal of Pharmacology, 33, 13–18.
21.
ZhangYH, ShinJS, LeeSS, LeeMK. (1997) Inhibition of tyrosine hydroxylase by bulbocapnine. Planta Medica, 63, 362–363.
22.
ShinJS, KimKT, LeeMK. (1998) Inhibitory effects of bulbocapnine on dopamine biosynthesis in PC12 cells. Neuroscience Letters, 244, 161–164.
23.
KohliJD, GlockD, GoldbergLI. (1986) Bulbocapnine is not a selective DA1 receptor antagonist. Journal of Pharmacy and Pharmacology, 38, 401–402.
24.
SpeiskyH, CasselsBK, SanhuezaV, NietoS, ValenzuelaA, Núñez-VergaraLJ. (1993) Determination of boldine in plasma by high-performance liquid chromatography. Journal of Chromatography – Biomedical Applications, 612, 315–319.
25.
JiménezI, SpeiskyH. (2000) Biological disposition of boldine: in vitro and in vivo studies. Phytotherapy Research, 14, 254–260.
26.
BhakuniDS, TewariS, KapilRS. (1977) Biosynthesis of boldine. Journal of the Chemical Society, Perkin Transactions 1, 706–709.
27.
TschescheR, WelzelP, MollR, LeglerG. (1964) über 2 Alkaloide aus der Rinde von Symplocos celastrinea Mart. Tetrahedron, 20, 1435–1438.
28.
AsencioM, CasselsBK, SpeiskyH. (1993) The methylation of boldine with diazomethane. Boletín de la Sociedad Chilena de Química, 38, 331–334.
29.
Sobarzo-SánchezEM, CasselsBK, Saitz-BarríaC, JullianC. (2001) Oxazine- and oxazole-fused derivatives of the alkaloid boldine and their complete structural and spectral assignment by HMQC and HMBC experiments. Magnetic Resonance in Chemistry, 39, 361–366.
30.
AsencioM. (2002) Chemistry of aporphinoids and relationships between their structures and their antioxidant and monoaminergic activities. PhD Thesis, University of Chile.
31.
PetkovV, TodorovS, GeorgievV, PetkovaB, DonevN. (1979) Pharmacological studies of a group of semi-synthetic structural analogues of glaucine. Acta Physiologica et Pharmacologica Bulgarica, 5, 3–12.
32.
OralloF, Fernández AlzuetaA, LozaMI, VivasN, BadíaA, CamposM, HonrubiaMA, CadavidMI. (1993) Study of the mechanism of the relaxant action of (+)-glaucine in rat vas deferens. British Journal of Pharmacology, 110, 943–948.
33.
OralloF, Fernández AlzuetaA, Campos-ToimilM, CallejaJM. (1995) Study of the in vivo and in vitro cardiovascular effects of (+)-glaucine and N-carbethoxysecoglaucine in rats. British Journal of Pharmacology, 114, 1419–1427.
34.
De las HerasB, RíosJL, Martínez-MirI, RubioE. (1990) A study of the adrenergic activity of the alkaloids boldine and glaucine. Die Pharmazie, 454, 443–444.
35.
IvorraMD, ChuliáS, LugnierC, D'OconMP. (1993) Selective action of two aporphines at alpha 1-adrenoceptors and potential-operated Ca2+ channels. European Journal of Pharmacology, 231, 165–174.
36.
IvorraMD, LugnierC, SchottC, CatretM, NogueraMA, AnselmiE, D'OconO. (1992) Multiple actions of glaucine on cyclic nucleotide phosphodiesterases, alpha 1-adrenoceptor and benzothiazepine binding site at the calcium channel. British Journal of Pharmacology, 106, 387–394.
37.
LozaI, OralloF, VerdeI, Gil-LongoJ, CadavidI, CallejaJM. (1995) A study of glaucine-induced relaxation of rat aorta. Planta Medica, 59, 229–231.
38.
IvorraMD, MartínezF, SerranoA, D'OconP. (1993) Different mechanism of relaxation induced by aporphine alkaloids in rat uterus. Journal of Pharmacy and Pharmacology, 45, 439–443.
39.
ChuliáS, MoreauJ, NalineE, NogueraMA, IvorraMD, D'OcónP, AdvenierC. (1996) The effect of S-(+)-boldine on the alpha 1-adrenoceptor of the guinea-pig aorta. British Journal of Pharmacology, 119, 1305–1312.
40.
MadreroY, ElorriagaM, MartínezS, NogueraMA, CasselsBK, D'OcónP, IvorraMD. (1996) A possible structural determinant of selectivity of boldine and derivatives for the alpha 1-adrenoceptor subtype. British Journal of Pharmacology, 119, 1563–1568.
41.
FabeiroP, ÁlvarezE, OralloF. (1999) Comparative study of the vasodilator effects of (+)-boldine, an alkaloid isolated from Peumus boldus, in rat small mesenteric arteries and rat aorta. Methods and Findings in Experimental and Clinical Pharmacology, 21 (Supplement A), 73.
42.
FabeiroP, ÁlvarezE, PinaR, OralloF. (2000) Comparative study of the in vivo and in vitro α1- and α2-adrenergic receptor blocking activity of (+)-boldine in normotensive rats. Methods and Findings in Experimental and Clinical Pharmacology, 22, 517.
43.
EltzeM, GrebeT, MichelMC, CzyborraP, UlrichB. (2002) Affinity profile at α1- and α2-adrenoceptor subtypes and in vitro cardiovascular actions of (+)-boldine. European Journal of Pharmacology, 443, 151–168.
44.
MartínezS, MadreroY, ElorriagaM, NogueraM-A, CasselsBK, SobarzoE, D'OconP, IvorraMD. (1999) Halogenated derivatives of boldine with high selectivity for α1A-adrenoceptors in rat cerebral cortex. Life Sciences, 64, 1205–1214.
45.
IvorraMD, ValienteM, MartínezS, MadreroY, NogueraMA, CasselsBK, SobarzoEM, D'OconP. (2005) 8-NH2-boldine, an antagonist of alpha1A and alpha1B adrenoceptors without affinity for the alpha1D subtype: structral requirements for aporphines at alpha1-adrenoceptor subtypes. Planta Medica, 71, 897–903.
46.
FullerBB, DrakeMA, SpauldingDT, ChaudhryF. (2000) Downregulation of tyrosinase activity in human melanocyte cell cultures by yohimbine. Journal of Investigative Dermatology, 115, 268–276.
47.
Mas-ChamberlinC, PeschardO, LerouxR, MondonP, LamyF, LintnerK. (2004) Di-acetyl-nor-aporphines: novel molecules and novel mechanism to inhibit melanogenesis. SÖFW-Journal, 130, 2–10.
48.
TengCM, YuSM, KoFN, ChenCC, HuangYL, HuangTF. (1991) Dicentrine, a natural vascular alpha 1-adrenoceptor antagonist, isolated from Lindera megaphylla. British Journal of Pharmacology, 104, 651–656.
49.
YuSM, HsuSY, KoFN, ChenCC, HuangYL, HuangTF, TengCM. (1992) Haemodynamic effects of dicentrine, a novel alpha 1-adrenoceptor antagonist: comparison with prazosin in spontaneously hypertensive and normotensive Wistar-Kyoto rats. British Journal of Pharmacology, 106, 797–801.
50.
SuMJ, NiehYC, HuangHW, ChenCC. (1994) Dicentrine, an alpha-adrenoceptor antagonist with sodium and potassium channel blocking activities. Naunyn-Schmiedebergs Archives of Pharmacology, 349, 42–49.
51.
MustafaMR, AchikeFI. (2000) Dicentrine is preferentially antagonistic to rat aortic than splenic alpha 1-adrenoceptor stimulation. Acta Pharmacologica Sinica, 21, 1165–1168.
52.
OralloF, AlzuetaAF. (2001) Preliminary study of the vasorelaxant effects of (+)-nantenine, an alkaloid isolated from Platycapnos spicata, in rat aorta. Planta Medica, 67, 800–806.
53.
RibeiroRdeA, do CarmoLG, VladimirovaI, JurkiewiczNH, JurkiewiczA. (2003) Nantenine blocks muscle contraction and Ca2+ transient induced by noradrenaline and K+ in rat vas deferens. European Journal of Pharmacology, 470, 37–43.
54.
OralloF. (2003) Pharmacological effects of (+)-nantenine, an alkaloid isolated from Platycapnos spicata, in several rat isolated tissues. Planta Medica, 69, 135–142.
55.
TsuchidaH, OhizumiY. (2003) (+)-Nantenine isolated from Nandina domestica Thunb. inhibits adrenergic pressor responses in pithed rats. European Journal of Pharmacology, 477, 53–58.
56.
OralloF. (2004) Acute cardiovascular effects of (+)-nantenine, an alkaloid isolated from Platycapnos spicata, in anaesthetised normotensive rats. Planta Medica, 70, 117–126.
57.
GuhJ-H, KoF-N, YuS-M, WuY-C, TengC-M. (1995) Pharmacological evaluation of N-metylactinodaphnine, a new vascular α-adrenoceptor antagonist, isolated from Illigera luzonensis. European Journal of Pharmacology, 279, 33–41.
58.
ChangC-W, KoF-N, SuM-J, WuY-C, TengC-M. (1997) Pharmacological evaluation of ocoteine, isolated from Cassytha filiformis, as an α1-adrenoceptor antagonist in rat thoracic aorta. Japanese Journal of Pharmacology, 73, 207–214.
59.
SotníkováR, KettmannV, KostálováD, TáborskáE. (1997) Relaxant properties of some aporphine alkaloids from Mahonia aquifolium. Methods and Findings in Experimental and Clinical Pharmacology, 19, 589–597.
60.
ChuliáS, NogueraMA, IvorraMD, CortesD, D'OcónMP. (1995) Vasodilator effects of liriodenine and norushinsunine, two aporphine alkaloids isolated from Annona cherimolia, in rat aorta. Pharmacology, 50, 380–387.
61.
ChuliáS, IvorraMD, CavéA, CortésD, NogueraMA, D'OcónP. (1995) Relaxant activity of three aporphine alkaloids from Annona cherimolia on isolated aorta of rat. Journal of Pharmacy and Pharmacology, 47, 647–650.
62.
ValienteM, D'OconP, NogueraMA, CasselsBK, LugnierC, IvorraMD. (2004) Vascular activity of (-)-anonaine, (-)-roemerine and (-)-pukateine, three natural 6a(R)-1,2-methylenedioxyaporphines with different affinities for α1-adrenoceptor subtypes. Planta Medica, 70, 603–609.
63.
ShojiN, UmeyamaA, TakemotoT., OhizumiY. (1984) Serotonergic receptor antagonist from Nandina domestica Thunberg. Journal of Pharmaceutical Sciences, 73, 568–570.
64.
IndraB, TadanoT, NakagawasaiO, AraiY, YasuharaH, OhizumiY, KisaraK. (2002) Suppressive effect of nantenine, isolated from Nandina domestica Thunberg, on the 5-hydroxy-L-tryptophan plus clorgyline-induced head-twitch response in mice. Life Sciences, 70, 2647–2656.
65.
RibeiroRA, Rodríguez de LoresArnaizG. (2000) Nantenine and papaverine differentially modify synaptosomal membrane enzymes. Phytomedicine, 7, 313–323.
66.
RibeiroRA, Rodríguez de LoresArnaiz G. (2001) In vitro dose dependent inverse effect of nantenine on synaptosomal membrane K+-p-NPPase activity. Phytomedicine, 8, 107–111.
67.
RibeiroRA, LeiteJR. (2003) Nantenine alkaloid presents anticonvulsant effect on two classical animal models. Phytomedicine, 10, 563–568.
68.
FantegrossiWE, KiesselCL, LeachPT, van MartinC, KarabenickRL, ChenX, OhizumiY, UllrichT, RiceKC, WoodsJH. (2004) Nantenine: an antagonist of the behavioral and physiological effects of MDMA in mice. Psychopharmacology (Berlin), 173, 270–277.
69.
GafnerS, DietzBM, McPhailKL, ScottIM, GlinskiJA, RussellFE, McCollomMM, BudzinskiJW, FosterBC, BergeronC, RhyuM-R, BoltonJL. (2006) Alkaloids from Eschscholtzia californica and their capacity to inhibit binding of [3H]8-hydroxy-2-(di-N-propylamino)tetralin to 5-HT1A receptors in vitro. Journal of Natural Products, 69, 432–435.
70.
CatretM, IvorraMD, D'OcónMP, AnselmiE. (1998) The 5-HT and alpha-adrenoceptor effect of four benzylisoquinoline alkaloids on rat aorta. Journal of Pharmacy and Pharmacology, 50, 317–322.
71.
LiHL, ZhangRP, YeHT, WangH. (2000) Effect of dicentrine on contraction of rat stomach muscle strips. Zhongguo Zhong Yao Za Zhi, 25, 426–428.
72.
IndraB, MatsunagaK, HoshinoO, SuzukiM, OgasawaraH, IshiguroM, OhizumiY. (2002) Structure-activity relationship on (±)-nantenine derivatives in antiserotonergic activities in rat aorta. Canadian Journal of Physiology and Pharmacology, 80, 198–204.
73.
IndraB, MatsunagaK, HoshinoO, SuzukiM, OgasawaraH, OhizumiY. (2002) Structure-activity relationship studies with (±)-nantenine derivatives for α1-adrenoceptor antagonist activity. European Journal of Pharmacology, 437, 173–178.
74.
IndraB, MatsunagaK, HoshinoO, SuzukiM, OgasawaraH, MuramatsuI, TaniguchiT, OhizumiY. (2002) (±)-Domesticine, a novel and selective α1D-adrenoceptor antagonist in animal tissues and human α1-adrenoceptors. European Journal of Pharmacology, 445, 21–29.
ErhardtPA, SoineTO. (1975) Stereochemical preferences for curaremimetic neuromuscular junction blockade. I. Enantiomeric monoquaternary amines as probes. Journal of Pharmaceutical Sciences, 64, 53–62.
77.
YuSM, LeeSS, HouYS, ChenCM. (1994) Mechanisms of vasorelaxation induced by N-allylsecoboldine in rat thoracic aorta. Naunyn-Schmiedebergs Archives of Pharmacology, 349, 637–643.
78.
GuhJ-H, HsiehC-H, TengC-M. (1999) Investigation of the effects of some alkaloidal α1-adrenoceptor antagonists on human hyperplastic prostate. European Journal of Pharmacology, 374, 503–510.
FrantzS. (2005) Playing dirty. Nature, 437, 942–943.
81.
van der SchyfCJ, GeldenhuysWJ, YoudimMB. (2006) Multifunctional drugs with different CNS targets for neuropsychiatric disorders. Journal of Neurochemistry, 99, 1033–1048.
82.
RothBL, ShefflerDJ, KroezeWK. (2004) Magic shotguns versus magic bullets: selectively non-selective drugs for mood disorders and schizophrenia. Nature Reviews in Drug Discovery, 3, 353–359.
83.
IchikawaJ, IshiiH, BonaccorsoS, FowlerWL, O'LaughlinIA, MeltzerHY. (2001) 5-HT2A and D2 receptor blockade increases cortical DA release via 5-HT1A receptor activation: a possible mechanism of atypical antipsychotic-induced cortical dopamine release. Journal of Neurochemistry, 76, 1521–1531.
84.
Bruins SlotLA, KlevenMS, Newman-TancrediA. (2005) Effects of novel antipsychotics with mixed D2 antagonist/5-HT1A agonist properties on PCP-induced social interaction deficits in the rat. Neuropharmacology, 49, 996–1006.
85.
BardinL, KlevenMS, Barret-GrévozC, DepoortèreR, Newman-TancrediA. (2006) Antipsychotic-like vs cataleptogenic actions in mice of novel antipsychotics having D2 antagonist and 5-HT1A agonist properties. Neuropsychopharmacology, 31, 1869–1879.
86.
AuclairAL, KlevenMS, BesnardJ, DepoortèreR, Newman-TancrediA. (2006) Actions of novel antipsychotic agents on apomorphine-induced PPI disruption: influence of combined serotonin 5-HT1A receptor activation and dopamine D2 receptor blockade. Neuropsychopharmacology, 31, 1900–1909.
87.
ZazpeA, ArtaizI, InnerárityA, del OlmoE, CastroE, LabeagaL, PazosA, OrjalesA. (2006) In vitro and in vivo characterization of F-97013-GD, a partial 5-HT1A agonist with antipsychotic- and antiparkinsonian-like properties. Neuropharmacology, 51, 129–140.