TiPS - April 1990 [Vol. II]
PRIAPISM MUST BE one of the rnost ill-named conditions in the lexicon of medicine. In Hellenic mythology, Priapus was the son of Aphrodite and Dionysus, later known as Venus and Bacchus. Priapus was the god of fertility, and hence the guardian of gardens. He was the chief deitv. of lasciviousness and obsceniry, and his distinguishil characteristic was an oversized phallus (Fig. 1). Priapism, however, is persistent and often painful erection unrelated to sexual desire or activity. The condition frequently results in impotence, and is considered a urological emergency. Between 30% and 50% of cases are drug induced (Table 1). It has been suggested that the increasing frequency of priapism is related to increased drug use and abuse’. Erection occurs by a varying combination of reflexogenic and psychogenic mechanisms*. The first type is due to local stimulation and is mediated through the afferent fibers of the pudendal nerve controlling parasympathetic outflow from the sacral spinal cord via the pelvic nerve. This mechanism, triggered by bladder pressure, is responsible for the erections typically experienced by men on waking. Psychogenic mechanisms are mediated via hypothalamic projections to the thoracolumnar spinal cord which control sympathetic and sacral parasympathetic outflow. Erections caused by exposure to pornography involve this mechanism. Ultimately, of course, an erection results from arterial flow into the penis exceeding venous flow out. The relative flows are controlled by the contractile state of smooth muscle in the vasculature and around the corpora cavernosum, where the blood is pooled, Fig. 1. Priapus pouring a libation to leading to engorgement. In priahis own fertiky (bronze from fhe 1st pism, prolonged stagnation of the century AD). engorged blood leads to a fall in oxygen content, increasing the viscosity. Eventually, fibrosis and cannabis and black widow spider impotence result. venom3 (Table 1). The drug-induced erections The pharmacology of erection is resulting in priapism are typically extraordinarily complex and poorly due to local effects on nerveunderstood. Adrenergic, cholinsmooth muscle interaction. Major ergic, serotonergic and peptidcrclasses of drug causing priapism gic systems are involved, and it is include psychotropics such as the difficult to tease these apart. Howphenothiazines, antihypertensives ever, one fairly well established and anticoagulants plus miscelmechanism of drug-induced prialaneous agents such as ethanol,
pism involves LX,-adrenoceptor blockade. lntracavemosal injection of the al-adrenoceptor antagonist phenoxybenzamine induces erections in humans which are reversed by the cw-adrenoceptor agonist metaraminol. Metaraminol, injected into the corpus cavemosum, has been used successfully to treat priapism4. Blockade of cul-adrenoceptors relaxes smooth muscle. The receptors involved are located on cavemosal trebecular smooth muscle (controlling the capacitance of the cavemosum) and the smooth muscle of the deep penile artery5. This implies that erection following a,-adrenoceptor blockade results from increased arterial flow and increased corporal capacity. Engorgement sustains erection by mechanical compression of venules, leading to decreased venous outflow. Elucidation of the cw-adrenergic mechanism of priapism has allowed a therapy for erectile impotence. This is a major disorder, affecting some ten million Americans6. Typically, phenoxybenzamine5 or phentolamine7 are given intracorporeally. Phentolamine alone, however, produces an erection that is inconvenieritly brief. It is given simultaneously with the muscle reiaxant, papaverine. In 67% of subjects, a firm erection is produced lasting an average 3.5 hours. This action of papaverine was discovered on accidental injection, when an TABLE I. Drugs inducing priapism Centrally acting drugs Phenothiazines Butyrophenones Antidepressants Hypnotics Other
(chlorpromazine, lrifluopromazine) (haloperidol) (phenelzine, trazodone) ;;;;n;;ualone) e . cannabis)
Antihypertensives Phenoxybenzamine, prazosin, hydralazine Anticoagulants Heparin, warfarin Miscellaneous Black widow spider venom, papaverine, ohentolamine. testosterone Adapted from Ref. 3
TiPS - April 2990 [Vol. 111
144
depressants, trazodone is unique in causing priapismr”. Trazodone is metabolized to the 5-HT receptor agonist, m-chlorophenylpiperazine. This substance produces erections in monkeys which are blocked by the 5-IIT receptor antagonist metergoline”. There are persistent reports of priapism associated with the use of the anticoagulant heparin3. The mechanism is obscure. Possi-
bilities include increased vasodilatation, or rebound thrombosis following discontinuation of heparin, perhaps due to changed platelet function 12. Or, given that other anticoagulants such as warfarin have also been associated with priapism, it could be that the priapism is the result of the underlying vascular condition for which anticoagulants are being administered.
AS SUGGESTED by the verse below, the medicinal leech, Wirulio medicinalis, began to vanish from its range some time ago. H. medicinalis is one of eleven freshwater species found in the UK (Fig. 2). Once common, in the wild it is now confined to the New Forest. Although the use of leeches for bloodletting has an extensive history, the practice all but died in this century. Leeches, however, are now undergoing a triumphant resurgence. The He with a smile then did his three inch (75 mm) long leech words repeat; is a cornucopia of pharmacoAnd said that, gathering logical agents. Leech comleeches, far and wide pounds under study include an He travelled; stirring thus a local anesanticoa~~ant, about his feet thetic, a vasodilator and an The waters of the pool where they abide. antibiotic, all compounds use‘Once I could meet with them ful to their producer’s bloodon eve y side; sucking propensities, and all But they have dwindled long compounds capable of being by slow decay; turned to therapeutic advanYet still I persevere, and find tage. them where 1 may.’ The best known compound is Wordsworth, hirudini3, briefly reviewed in Resolution and Independence, 1802 TiPS in 198814. This 7 kDa polypeptide of 65 residues is a selective inhibitor of thrombin, interyear-old boy who had been bitten rupting thrombin-induced plateby a dog. let activation. H&din is now E:‘. ~ledi~inalis is yet another of available from recombinant gene th\sse species until recently untechnologyls. It can be used as considered that are now sources prophylaxis for stasis-induced of valuable agents. We can only venous thrombosis and arterial speculate as to what has been thrombosis without increasing irretrievably lost with the vast and hemorrhagic risk. accelerating number of manThe Mexican leech, ~ae~e~te~a induced extinctions of plants, officinalis, is the source of a 15 kDa protein, antistatinlb. This 119 residue anticoagulant protein is an inhibitor of factor Xa, and shares no homology with hirudin. Leeches themselves are reoccupying their old piace in medicine. Biopharm Ltd is a British company raising leeches, which sell for $6 per specimen in the USA. They have particular application in microsurgery. This drew popular attention in 1985, when a Boston surgeon, Upton, used leeches as blood removers Fig.2. Themedicinal leech. and anticoagulators in the course of reattaching an ear to a five-
insects, animals and birds. It is a sad fact of human psychology that we miss what we have had but give little consideration to what we could have had. Occasionally, we are given some hint of what we have thoughtlessly destroyed. The gingko tree, glanced upon in an earlier column17, is one such. This tree, which appears to have escaped extinction ‘accidentally‘, is the source of several compounds of pha~a~ologic~ importance. Another species is the giant, 18-inch (4EmO mm) long Amazon leech; Haem enteria ghilianii, which was long thought to be extinct. The discovery of a few survivors in the remote swamps of French Guiana and their s&sequent cultivation has led to the isolation of a salivary enzyme, hemetin. This enzyme, unlike an anticoagulant which prevents clots from forming, will dissolve clots once th.ey are formed. The enzyme has been patented to Biopharm, and has potential valuable applications in the treatment of infarcts and other cardiovascular conditions. The Canadian writer Robertson Davies defines a Philistine as ‘someone who is content to live in a wholly unexplored world‘~s. ‘What use is it? the Philistine asks when he or she hears that the construction of a dam is threatening the survival of the snail darter, a small fish. However, use and uselessness are constructs of the mind, an artificial duality having no place in nature. The inability to see a use for an unconsidered and threatened species is a failure of imagination on the part of the observer, the same failure that saw the Atlantic as a vast and stormy waste bounding and limiting Europe rather than as ;a great highway to the undiscovered variety of the new world.
erection lasting 2 hours was produced*. The mechanism is problematic but may be a result of an increased capacitance of the Following cavemosa. corpora erection due to a-adrenoceptor blockade, if detumescence does not occur within a given period, metaraminol is given9. Activation of S-FIT receptors is another mechanism whereby priapism occurs. Of the tricyclic anti-
72’5 - April 1990 [Vol. 121
145
FIXATION OF CARBON DIOXIDE, or carboxylation, occurs in all green plants and is a process fundamental to life. One could define biochemistry as the study of carboxylation and its consequences. The opposite process of decarboxylation also occurs, about 70 decarboxylases having been characterized19. The typical decarboxylase is a pyridoxal-phosphate-dependent enzyme catalysing an irreversible step of ihe general type: RCOOH +
RH + CO2
However, where the substrate is an amino acid, decarboxylation is a step that transmutes bioc’ zmistry to pharmacology, inasmuch as the substrates are involved in primary metabolic processes such as protein synthesis while the products are secondary metabolites typically exhibiting high pharmacological activity (Table II): biochemistry - CO* + pharmacology The study of neurotransmitters and neuromodulators such as GABA, taurine, epinephrine, norepinephrine, dopamine and 5-HT has traditionally been considered the province of pharmacology. These are decarboxylated metabolites of amino acids. Decarboxylation of the acidic amino acids, glutamate and cysteine su!finate, converts these neuroexcitatory substances into the neuroinhibitory ar,o-amino acids, GABA, hypotaurine and taurine. As these amino acids typically are present in millimolar concentrations in brain, the decarboxylases mediating their transformation are crucially involved in the regulation of brain excitability. Seizures develop on inhibition of decarboxylase activity by pyridoxal phosphate deficiency or by other means. As their names indicate, subcadaverine, stances such as putrescine, spermine and spermidine have foully mephitic odors,
as does the tryptophan metabolite, 3-methylindole, or skatole. This latter compound is one of the major odorants of feces. Although it has been claimed that a rose by any other name would smell as sweet, the for.mation of these amines in decay raises the question as to whether we perceive them as having bad smells because their production indicates a health risk. The question is probably unanswerable, but the fact remains that decarboxylation associated with bacterial catab-
TABLE Ill. A selection of alkaloids derived from amino acids Amino acid precursor Alkaloidal class
Examples
Pharmacological action
Ornithine
pyrrolidine tropane
nicotine atropine
pyrrolizidine
cocaine monocrotaline
cholinomimetic muscarinic cholinoceptor antagonist local anesthetic hepatotoxin
piperidine quinoliziJine
slaframine sparteine
excessive salivation oxytocic
Lysine
mescaline ephedrine gliotoxin diketopiperazine papaverine benzyl isoquinoline bisbenzyl isoquinoline tubocurarine isothebaine aporphine colchicine
hallucinogen sympathomimetic bacteriostatic smooth muscle relaxant neuromuscular blockade increased muscle tone mitotic inhibitor
psilocybin tryptamine physostigmine physostigmine lysergic acid amide ergot monoterpenoid indole quinidine strychnine quinine yohimbine yohimbine
reserpine
hallucinogen cholinesterase inhibitor hallucinogen cardiac depressant convulsant antimalarial 5-HT receptor and cu,-adrenoceptor antagonist hypotensive
pilocarpine
parasympathomimetic
PhenylalanineAyrosine phenethylamine
Tryptophan
rauwolfia Histidine
Alkaloids may have more actions than the one listed.
TABLE II. Some amino acid decarboxylases EC number
Substrate
Initial product
4.1.1.15 4.1 .I 29 4.1.1.17 4.1.1.18 4.1.1.22 4.1 .I .25 4.1 .I .2a
glutamate cysteine sulfinate ornithine lysine histidine tyrosine tryptophan dopa
GABA hypotaurine putrescine cadaverine histamine tyramine tryptamine dopamine
5-Hydroxytryptophan phenylalanine methionine
5-HT phenylethylamine 3-methylthiopropylamine
4.1 .I .53 4.1 .I .57
olism and tissue breakdown produces substances that serve as powerful olfactory signals. The production of simple alkylamines in dead fish serves a similar function. The formation of histamine from histidine is probably responsible for more needless misery than any other biochemical process. Wind-borne plant pollens need characteristics that permit them to be selectively recognized by the stigmas of receptive flowers. The proteins conferring this ready recognizability to the pollen also, by happenstance, allow ready recognition by the immune systems of those preordained to suffer from the vernal florescence of nature. The resultant outpouring of histamine in an inefficient defense against a nonexistent threat produces the head-
Other products taurine spermidine. spermine
mescaline, morphine skaiole epinephrine, norepinephrine, melanin
watery eyes, sneezing, aches, runny nose, itching, disturbed sleep and general misery subsumed under the general term, hay fever. The product of another detyramine, limits carboxylation, many a person’s enjoyment of good cheeses and wines, and restricts the gastronomic pleasures of those taking monoamine oxidase inhibitors such as isoniazid, phenelzine or pargyline.
TiPS - April 2990 [Vol. 1 II
146 The most impressive and extensive group of secondary metabelites resulting from decarboxyl-
ation are the alkaloids. Most of this disparate group probably serve as plant defenses, their formation consti~ting one of the mechanisms whereby the highly successful angiosperms evolved in the face of predation by large bacterial viral, animals and and fungal onslaughts. The mammalian pharmacology of alkaloids is extensive; it is difficult to think of an alkaloid lacking in activity (Table III). Carboxylation and decarboxylation - these two processes, so simple in principle, have shaped and determined the respective
disc:plines
and
of biochemistry
pharmacology. 8.
MAX
References 1 winter, c. c. (1981) j. L&of. 125,212 2 Wasmer, 1. MM.,Carrion, H. M., Mekras, G. and Po&ano, V. A. (1981) J. UroI. 125, 204-207 3 Bafios, J. E., Bosch, F. and Far& M. (1989) Med. Toxicol. Adverse Dru.q Exper. 4,464 4 Starmers, A. and Colin-Jones, D. (1984) Latxrf ii, 978 5 Brindiey, G. S. (1983) Br. J. Ps~c;~iat~ 143,332-337 6 Krane, R. J., Goldstein, I. and Saenz de Tejada. I. (1989) N. Eql. I. Med. 321, 1648-1659 7 Ne!!ans, R. E., ELIis, L. R. and KramerLevien, D. (1987) J. Ural. 138, 52-54 8 Michal. V., Kramer, R., F’opischai,J. and
_ETTERS Dextromethoxphan, dysphoria and NMDA receptors
Neuromodulatoryeffects of dextromethorphan: role of NMDA receptors in responses I read with interest the recent article by Tortella and colleagues (Tips, December 1989)’ conceming the central actions of dextromethorphan. I agree with many of their points, but others require comment. Firstly, the authors’ statement that dextromethorphan is not psychotomimetic in humans is not supported by the literature. In addition to anecdotal reports of hallucinations following overdoses of proprietary cough medicines containing dextromethorphan, sporadic cases of dextromethorphan abuse in which patients reported dysphoric symptoms have been documented* and Jasinski et al. reported ‘defiiiiie subjective effects of a psychotomimetic nature’ (see references in Ref. 3). Behavioural similarities are also evident in animal studies, where dextromethorphan shares disc~minative effects with other PCP receptor Iigands’ at doses related closely to those that reduce NMDA receptor-mediated neuronal excitations in uivo5. Rather __._~
than being a possible ‘psychotomimetic antagonist’ (Ref. l), dextromethorphan therefore appears to share the adverse dysphoric effects of other PCP-like NMDA receptor antagonists’. Secondly, the authors ascribe a functionally important role to high affinity dextromethorphan and/or o-binding sites in the behavioural pharmacology of dextromethorphan. However, in the absence of a selective antagonist for the dextromethorphan (or a-) site, the establishment of a clear rank order potency for binding to these sites is necessary before one can infer, even indirectly, the possibility of a causal relationship between an action at either site and behavioural effects. Indeed, binding and behavioural data are available for only a limited series of o- OT dextromethorphan receptor ligands. Similarly, it would appear unwise to attempt to differentiate between the binding properties and the pharmacology in viva of dextromethorphan and a-si.te ligands on the basis of data
Hejhai, L. (1977) World 1. Szrrg.1,515 9 Brindley. G. S. (1984) Lmtcef ii, 220-221 10 Lansky, M. R. and Seizer, J. (1984) J. Clir~. Psyclriafry 45, 232-233 11 Aloi, J. A., Insel, T. R., Mueller, E. A. and Murphy, D. L. (1984) Life Sci. 34, 1325-1331 12 Burke, 8. J,, Smith, P. J. B., Scott, G. L. and Wakerley, 6. R. (1983) ~osfgrad. Med. f. 59,332-333 13 Markwardt, F. and Landmann, H. (1971) Hn,rdb. Exp. Pharmncol. 27, 76-142 14 Wallis, R. B. (1988) Trends Phnrmncol. Sci. 9, 425-427 15 Markwardt, F. et al. (198s) Pharnrazie43, 202-207 16 Nutt, E. rf ~1. (1988) J. Biol. Ckenr. 263, 1016%10167 17 Max, B. (1987) Trends Phnmmcol. Sci. 8, 290-292 18 Davies, R. (1989) The Lyre of Orphees, Viking 19 Webb, E. C., ed. (1984) Enzyme Nonlencfafure 1984, Academic Press
obtained with a small number of non-selective compounds. For example, as well as having affinity for the high affinity u site (Ref. I), (+)-SKF10047 [together with the (+)-isomers of other benzomorphans including pentazocine and cyclazocine] has affinity for the PCP receptor; all these drugs act as PCP-like interoceptive cues in animal studies; and all reduce neuronal excitations evoked by NMDA with a rank order of potency that by and large parallels their known behavioural effects5,‘. To use the observation that (+)SKF10047 is a more potent anticonvulsant but has less affinity for the o-site than (+)-pentazocine, to infer differences in the functional roles of high affinity dextromethorphan or u-sites may lead to misunderstandings. An equally tenable explanation is that (+)-SKF10047 is a more potent NMDA antagonist than (+)-pentazocine5. Thirdly, I cannot agree with mentioned the ‘inconsistencies’ regarding the role of NMDA antagonism in the pharmacology of dextromethorphan. The finding that NMDA receptor ligands fail to compete with the dextromethorphan site, for example, would only assume importance if this site mediated the NMDA antagonist effects of dextromethorphan. Similarly, that dextrorphan does not eompete for the high affinity dextromethorphan site whilst being anticonvulsant should cast doubt on the functional relevance of this site in
PRIAPISM MUST BE one of the rnost ill-named conditions in the lexicon of medicine. In Hellenic mythology, Priapus was the son of Aphrodite and Dionysus, later known as Venus and Bacchus. Priapus was the god of fertility, and hence the guardian of gardens. He was the chief deitv. of lasciviousness and obsceniry, and his distinguishil characteristic was an oversized phallus (Fig. 1). Priapism, however, is persistent and often painful erection unrelated to sexual desire or activity. The condition frequently results in impotence, and is considered a urological emergency. Between 30% and 50% of cases are drug induced (Table 1). It has been suggested that the increasing frequency of priapism is related to increased drug use and abuse’. Erection occurs by a varying combination of reflexogenic and psychogenic mechanisms*. The first type is due to local stimulation and is mediated through the afferent fibers of the pudendal nerve controlling parasympathetic outflow from the sacral spinal cord via the pelvic nerve. This mechanism, triggered by bladder pressure, is responsible for the erections typically experienced by men on waking. Psychogenic mechanisms are mediated via hypothalamic projections to the thoracolumnar spinal cord which control sympathetic and sacral parasympathetic outflow. Erections caused by exposure to pornography involve this mechanism. Ultimately, of course, an erection results from arterial flow into the penis exceeding venous flow out. The relative flows are controlled by the contractile state of smooth muscle in the vasculature and around the corpora cavernosum, where the blood is pooled, Fig. 1. Priapus pouring a libation to leading to engorgement. In priahis own fertiky (bronze from fhe 1st pism, prolonged stagnation of the century AD). engorged blood leads to a fall in oxygen content, increasing the viscosity. Eventually, fibrosis and cannabis and black widow spider impotence result. venom3 (Table 1). The drug-induced erections The pharmacology of erection is resulting in priapism are typically extraordinarily complex and poorly due to local effects on nerveunderstood. Adrenergic, cholinsmooth muscle interaction. Major ergic, serotonergic and peptidcrclasses of drug causing priapism gic systems are involved, and it is include psychotropics such as the difficult to tease these apart. Howphenothiazines, antihypertensives ever, one fairly well established and anticoagulants plus miscelmechanism of drug-induced prialaneous agents such as ethanol,
pism involves LX,-adrenoceptor blockade. lntracavemosal injection of the al-adrenoceptor antagonist phenoxybenzamine induces erections in humans which are reversed by the cw-adrenoceptor agonist metaraminol. Metaraminol, injected into the corpus cavemosum, has been used successfully to treat priapism4. Blockade of cul-adrenoceptors relaxes smooth muscle. The receptors involved are located on cavemosal trebecular smooth muscle (controlling the capacitance of the cavemosum) and the smooth muscle of the deep penile artery5. This implies that erection following a,-adrenoceptor blockade results from increased arterial flow and increased corporal capacity. Engorgement sustains erection by mechanical compression of venules, leading to decreased venous outflow. Elucidation of the cw-adrenergic mechanism of priapism has allowed a therapy for erectile impotence. This is a major disorder, affecting some ten million Americans6. Typically, phenoxybenzamine5 or phentolamine7 are given intracorporeally. Phentolamine alone, however, produces an erection that is inconvenieritly brief. It is given simultaneously with the muscle reiaxant, papaverine. In 67% of subjects, a firm erection is produced lasting an average 3.5 hours. This action of papaverine was discovered on accidental injection, when an TABLE I. Drugs inducing priapism Centrally acting drugs Phenothiazines Butyrophenones Antidepressants Hypnotics Other
(chlorpromazine, lrifluopromazine) (haloperidol) (phenelzine, trazodone) ;;;;n;;ualone) e . cannabis)
Antihypertensives Phenoxybenzamine, prazosin, hydralazine Anticoagulants Heparin, warfarin Miscellaneous Black widow spider venom, papaverine, ohentolamine. testosterone Adapted from Ref. 3
TiPS - April 2990 [Vol. 111
144
depressants, trazodone is unique in causing priapismr”. Trazodone is metabolized to the 5-HT receptor agonist, m-chlorophenylpiperazine. This substance produces erections in monkeys which are blocked by the 5-IIT receptor antagonist metergoline”. There are persistent reports of priapism associated with the use of the anticoagulant heparin3. The mechanism is obscure. Possi-
bilities include increased vasodilatation, or rebound thrombosis following discontinuation of heparin, perhaps due to changed platelet function 12. Or, given that other anticoagulants such as warfarin have also been associated with priapism, it could be that the priapism is the result of the underlying vascular condition for which anticoagulants are being administered.
AS SUGGESTED by the verse below, the medicinal leech, Wirulio medicinalis, began to vanish from its range some time ago. H. medicinalis is one of eleven freshwater species found in the UK (Fig. 2). Once common, in the wild it is now confined to the New Forest. Although the use of leeches for bloodletting has an extensive history, the practice all but died in this century. Leeches, however, are now undergoing a triumphant resurgence. The He with a smile then did his three inch (75 mm) long leech words repeat; is a cornucopia of pharmacoAnd said that, gathering logical agents. Leech comleeches, far and wide pounds under study include an He travelled; stirring thus a local anesanticoa~~ant, about his feet thetic, a vasodilator and an The waters of the pool where they abide. antibiotic, all compounds use‘Once I could meet with them ful to their producer’s bloodon eve y side; sucking propensities, and all But they have dwindled long compounds capable of being by slow decay; turned to therapeutic advanYet still I persevere, and find tage. them where 1 may.’ The best known compound is Wordsworth, hirudini3, briefly reviewed in Resolution and Independence, 1802 TiPS in 198814. This 7 kDa polypeptide of 65 residues is a selective inhibitor of thrombin, interyear-old boy who had been bitten rupting thrombin-induced plateby a dog. let activation. H&din is now E:‘. ~ledi~inalis is yet another of available from recombinant gene th\sse species until recently untechnologyls. It can be used as considered that are now sources prophylaxis for stasis-induced of valuable agents. We can only venous thrombosis and arterial speculate as to what has been thrombosis without increasing irretrievably lost with the vast and hemorrhagic risk. accelerating number of manThe Mexican leech, ~ae~e~te~a induced extinctions of plants, officinalis, is the source of a 15 kDa protein, antistatinlb. This 119 residue anticoagulant protein is an inhibitor of factor Xa, and shares no homology with hirudin. Leeches themselves are reoccupying their old piace in medicine. Biopharm Ltd is a British company raising leeches, which sell for $6 per specimen in the USA. They have particular application in microsurgery. This drew popular attention in 1985, when a Boston surgeon, Upton, used leeches as blood removers Fig.2. Themedicinal leech. and anticoagulators in the course of reattaching an ear to a five-
insects, animals and birds. It is a sad fact of human psychology that we miss what we have had but give little consideration to what we could have had. Occasionally, we are given some hint of what we have thoughtlessly destroyed. The gingko tree, glanced upon in an earlier column17, is one such. This tree, which appears to have escaped extinction ‘accidentally‘, is the source of several compounds of pha~a~ologic~ importance. Another species is the giant, 18-inch (4EmO mm) long Amazon leech; Haem enteria ghilianii, which was long thought to be extinct. The discovery of a few survivors in the remote swamps of French Guiana and their s&sequent cultivation has led to the isolation of a salivary enzyme, hemetin. This enzyme, unlike an anticoagulant which prevents clots from forming, will dissolve clots once th.ey are formed. The enzyme has been patented to Biopharm, and has potential valuable applications in the treatment of infarcts and other cardiovascular conditions. The Canadian writer Robertson Davies defines a Philistine as ‘someone who is content to live in a wholly unexplored world‘~s. ‘What use is it? the Philistine asks when he or she hears that the construction of a dam is threatening the survival of the snail darter, a small fish. However, use and uselessness are constructs of the mind, an artificial duality having no place in nature. The inability to see a use for an unconsidered and threatened species is a failure of imagination on the part of the observer, the same failure that saw the Atlantic as a vast and stormy waste bounding and limiting Europe rather than as ;a great highway to the undiscovered variety of the new world.
erection lasting 2 hours was produced*. The mechanism is problematic but may be a result of an increased capacitance of the Following cavemosa. corpora erection due to a-adrenoceptor blockade, if detumescence does not occur within a given period, metaraminol is given9. Activation of S-FIT receptors is another mechanism whereby priapism occurs. Of the tricyclic anti-
72’5 - April 1990 [Vol. 121
145
FIXATION OF CARBON DIOXIDE, or carboxylation, occurs in all green plants and is a process fundamental to life. One could define biochemistry as the study of carboxylation and its consequences. The opposite process of decarboxylation also occurs, about 70 decarboxylases having been characterized19. The typical decarboxylase is a pyridoxal-phosphate-dependent enzyme catalysing an irreversible step of ihe general type: RCOOH +
RH + CO2
However, where the substrate is an amino acid, decarboxylation is a step that transmutes bioc’ zmistry to pharmacology, inasmuch as the substrates are involved in primary metabolic processes such as protein synthesis while the products are secondary metabolites typically exhibiting high pharmacological activity (Table II): biochemistry - CO* + pharmacology The study of neurotransmitters and neuromodulators such as GABA, taurine, epinephrine, norepinephrine, dopamine and 5-HT has traditionally been considered the province of pharmacology. These are decarboxylated metabolites of amino acids. Decarboxylation of the acidic amino acids, glutamate and cysteine su!finate, converts these neuroexcitatory substances into the neuroinhibitory ar,o-amino acids, GABA, hypotaurine and taurine. As these amino acids typically are present in millimolar concentrations in brain, the decarboxylases mediating their transformation are crucially involved in the regulation of brain excitability. Seizures develop on inhibition of decarboxylase activity by pyridoxal phosphate deficiency or by other means. As their names indicate, subcadaverine, stances such as putrescine, spermine and spermidine have foully mephitic odors,
as does the tryptophan metabolite, 3-methylindole, or skatole. This latter compound is one of the major odorants of feces. Although it has been claimed that a rose by any other name would smell as sweet, the for.mation of these amines in decay raises the question as to whether we perceive them as having bad smells because their production indicates a health risk. The question is probably unanswerable, but the fact remains that decarboxylation associated with bacterial catab-
TABLE Ill. A selection of alkaloids derived from amino acids Amino acid precursor Alkaloidal class
Examples
Pharmacological action
Ornithine
pyrrolidine tropane
nicotine atropine
pyrrolizidine
cocaine monocrotaline
cholinomimetic muscarinic cholinoceptor antagonist local anesthetic hepatotoxin
piperidine quinoliziJine
slaframine sparteine
excessive salivation oxytocic
Lysine
mescaline ephedrine gliotoxin diketopiperazine papaverine benzyl isoquinoline bisbenzyl isoquinoline tubocurarine isothebaine aporphine colchicine
hallucinogen sympathomimetic bacteriostatic smooth muscle relaxant neuromuscular blockade increased muscle tone mitotic inhibitor
psilocybin tryptamine physostigmine physostigmine lysergic acid amide ergot monoterpenoid indole quinidine strychnine quinine yohimbine yohimbine
reserpine
hallucinogen cholinesterase inhibitor hallucinogen cardiac depressant convulsant antimalarial 5-HT receptor and cu,-adrenoceptor antagonist hypotensive
pilocarpine
parasympathomimetic
PhenylalanineAyrosine phenethylamine
Tryptophan
rauwolfia Histidine
Alkaloids may have more actions than the one listed.
TABLE II. Some amino acid decarboxylases EC number
Substrate
Initial product
4.1.1.15 4.1 .I 29 4.1.1.17 4.1.1.18 4.1.1.22 4.1 .I .25 4.1 .I .2a
glutamate cysteine sulfinate ornithine lysine histidine tyrosine tryptophan dopa
GABA hypotaurine putrescine cadaverine histamine tyramine tryptamine dopamine
5-Hydroxytryptophan phenylalanine methionine
5-HT phenylethylamine 3-methylthiopropylamine
4.1 .I .53 4.1 .I .57
olism and tissue breakdown produces substances that serve as powerful olfactory signals. The production of simple alkylamines in dead fish serves a similar function. The formation of histamine from histidine is probably responsible for more needless misery than any other biochemical process. Wind-borne plant pollens need characteristics that permit them to be selectively recognized by the stigmas of receptive flowers. The proteins conferring this ready recognizability to the pollen also, by happenstance, allow ready recognition by the immune systems of those preordained to suffer from the vernal florescence of nature. The resultant outpouring of histamine in an inefficient defense against a nonexistent threat produces the head-
Other products taurine spermidine. spermine
mescaline, morphine skaiole epinephrine, norepinephrine, melanin
watery eyes, sneezing, aches, runny nose, itching, disturbed sleep and general misery subsumed under the general term, hay fever. The product of another detyramine, limits carboxylation, many a person’s enjoyment of good cheeses and wines, and restricts the gastronomic pleasures of those taking monoamine oxidase inhibitors such as isoniazid, phenelzine or pargyline.
TiPS - April 2990 [Vol. 1 II
146 The most impressive and extensive group of secondary metabelites resulting from decarboxyl-
ation are the alkaloids. Most of this disparate group probably serve as plant defenses, their formation consti~ting one of the mechanisms whereby the highly successful angiosperms evolved in the face of predation by large bacterial viral, animals and and fungal onslaughts. The mammalian pharmacology of alkaloids is extensive; it is difficult to think of an alkaloid lacking in activity (Table III). Carboxylation and decarboxylation - these two processes, so simple in principle, have shaped and determined the respective
disc:plines
and
of biochemistry
pharmacology. 8.
MAX
References 1 winter, c. c. (1981) j. L&of. 125,212 2 Wasmer, 1. MM.,Carrion, H. M., Mekras, G. and Po&ano, V. A. (1981) J. UroI. 125, 204-207 3 Bafios, J. E., Bosch, F. and Far& M. (1989) Med. Toxicol. Adverse Dru.q Exper. 4,464 4 Starmers, A. and Colin-Jones, D. (1984) Latxrf ii, 978 5 Brindiey, G. S. (1983) Br. J. Ps~c;~iat~ 143,332-337 6 Krane, R. J., Goldstein, I. and Saenz de Tejada. I. (1989) N. Eql. I. Med. 321, 1648-1659 7 Ne!!ans, R. E., ELIis, L. R. and KramerLevien, D. (1987) J. Ural. 138, 52-54 8 Michal. V., Kramer, R., F’opischai,J. and
_ETTERS Dextromethoxphan, dysphoria and NMDA receptors
Neuromodulatoryeffects of dextromethorphan: role of NMDA receptors in responses I read with interest the recent article by Tortella and colleagues (Tips, December 1989)’ conceming the central actions of dextromethorphan. I agree with many of their points, but others require comment. Firstly, the authors’ statement that dextromethorphan is not psychotomimetic in humans is not supported by the literature. In addition to anecdotal reports of hallucinations following overdoses of proprietary cough medicines containing dextromethorphan, sporadic cases of dextromethorphan abuse in which patients reported dysphoric symptoms have been documented* and Jasinski et al. reported ‘defiiiiie subjective effects of a psychotomimetic nature’ (see references in Ref. 3). Behavioural similarities are also evident in animal studies, where dextromethorphan shares disc~minative effects with other PCP receptor Iigands’ at doses related closely to those that reduce NMDA receptor-mediated neuronal excitations in uivo5. Rather __._~
than being a possible ‘psychotomimetic antagonist’ (Ref. l), dextromethorphan therefore appears to share the adverse dysphoric effects of other PCP-like NMDA receptor antagonists’. Secondly, the authors ascribe a functionally important role to high affinity dextromethorphan and/or o-binding sites in the behavioural pharmacology of dextromethorphan. However, in the absence of a selective antagonist for the dextromethorphan (or a-) site, the establishment of a clear rank order potency for binding to these sites is necessary before one can infer, even indirectly, the possibility of a causal relationship between an action at either site and behavioural effects. Indeed, binding and behavioural data are available for only a limited series of o- OT dextromethorphan receptor ligands. Similarly, it would appear unwise to attempt to differentiate between the binding properties and the pharmacology in viva of dextromethorphan and a-si.te ligands on the basis of data
Hejhai, L. (1977) World 1. Szrrg.1,515 9 Brindley. G. S. (1984) Lmtcef ii, 220-221 10 Lansky, M. R. and Seizer, J. (1984) J. Clir~. Psyclriafry 45, 232-233 11 Aloi, J. A., Insel, T. R., Mueller, E. A. and Murphy, D. L. (1984) Life Sci. 34, 1325-1331 12 Burke, 8. J,, Smith, P. J. B., Scott, G. L. and Wakerley, 6. R. (1983) ~osfgrad. Med. f. 59,332-333 13 Markwardt, F. and Landmann, H. (1971) Hn,rdb. Exp. Pharmncol. 27, 76-142 14 Wallis, R. B. (1988) Trends Phnrmncol. Sci. 9, 425-427 15 Markwardt, F. et al. (198s) Pharnrazie43, 202-207 16 Nutt, E. rf ~1. (1988) J. Biol. Ckenr. 263, 1016%10167 17 Max, B. (1987) Trends Phnmmcol. Sci. 8, 290-292 18 Davies, R. (1989) The Lyre of Orphees, Viking 19 Webb, E. C., ed. (1984) Enzyme Nonlencfafure 1984, Academic Press
obtained with a small number of non-selective compounds. For example, as well as having affinity for the high affinity u site (Ref. I), (+)-SKF10047 [together with the (+)-isomers of other benzomorphans including pentazocine and cyclazocine] has affinity for the PCP receptor; all these drugs act as PCP-like interoceptive cues in animal studies; and all reduce neuronal excitations evoked by NMDA with a rank order of potency that by and large parallels their known behavioural effects5,‘. To use the observation that (+)SKF10047 is a more potent anticonvulsant but has less affinity for the o-site than (+)-pentazocine, to infer differences in the functional roles of high affinity dextromethorphan or u-sites may lead to misunderstandings. An equally tenable explanation is that (+)-SKF10047 is a more potent NMDA antagonist than (+)-pentazocine5. Thirdly, I cannot agree with mentioned the ‘inconsistencies’ regarding the role of NMDA antagonism in the pharmacology of dextromethorphan. The finding that NMDA receptor ligands fail to compete with the dextromethorphan site, for example, would only assume importance if this site mediated the NMDA antagonist effects of dextromethorphan. Similarly, that dextrorphan does not eompete for the high affinity dextromethorphan site whilst being anticonvulsant should cast doubt on the functional relevance of this site in
