Sibutramine: pharmacological profile

Sibutramine (BTS 54 524, N-{ I-[l-(4-electrophenyl)cyclobutyl]-3-methylbuthyl} -N, N-dimethylamine HCl monohydrate, Meridia®, Reductil®) is a noradrenaline and 5-HT reuptake inhibitor (SNRI) which was discovered in a search for a potent second- generation SNRI (antidepressant). In contrast to promising pre-clinical data, clinical trials did not confirm the efficacy of sibutramine as an anti depressant. However, unlike some tricyclic antidepressants which increase body weight (doxepine, amitriptyline), its anorectic properties were particularly remarkable. Therefore, it was decided that sibutramine should be developed as an anti-obesity agent.

Sibutramine induces weight loss by reducing food-intake (Jackson et al. 1997), through enhancement of satiety, and increasing energy expenditure by thermogenesis (Connoley et al. 1999). Unlike (/-amphetamine, sibutramine does not disrupt the “satiety sequence” (the pattern of behaviours accompanying feeding). When administered in rats at relevant doses, sibutramine accelerates the decline of feeding by reducing the duration and frequency of eating episodes. It also advances the onset and duration of resting which, in turn, reduces the duration of grooming, locomotion and rearing (Halford et al.

1995). Calorimetry experiments demonstrated that sibutramine also enhances thermogenesis (Connoley et al. 1999).

Chapter 1: General Introduction

As an anorectic agent, sibutramine is active via its metabolites: metabolite 1, the secondary amine, and metabolite 2, the primary amine. Metabolites 1 and 2 are highly potent inhibitors of monoamine reuptake in vitro (Table 1.4). In rat brain, they are nearly as potent as the selective noradrenaline reuptake inhibitor, desipramine, and the selective 5-HT reuptake inhibitor, fluoxetine. Although metabolites 1 and 2 are potent inhibitors of dopamine uptake in vitro, in vivo studies reported a clear difference in the relative uptake inhibition of noradrenaline and 5-HT, compared to dopamine. In a study comparing sibutramine with the dopamine reuptake inhibitor, bupropion, and the dopamine reuptake inhibitor and releasing agent, methamphetamine. Heal et al. (1992) found out that dopamine reuptake was unlikely to be an important pharmacological target for sibutramine.

Table 1.4. In vitro inhibition Ki o f drugs inhibiting monoamine reuptake.

Ki (nM) Noradrenaline 5-HT Dopamine Drug ₍₁₎ (2) (1) (2) (1) (2) (3) Sibutramine 283 1811 2309 542 Metabolite 1 2.7 17 24 17 Metabolite 2 4.9 25 31 26 Desipramine 4853 Fluoxetine 11 2025 cf-Amphetamine 45 39 1441 3830 132 34 78

Kv. inhibition constant; (1) data from Heal et al. 1998; results obtained from fronto-cortical preparations for noradrenaline and 5-HT, and from striatum preparations for dopamine; (2) data from Rothman et al. 2002; results obtained from preparations of the whole brain minus caudate and cerebellum for noradrenaline and dopamine, and from preparation of caudate for dopamine; (3) data from Rowley et al. (2000); results obtained from nucleus accumbens preparations.

Sibutramine potentiates monoaminergic function only via reuptake inhibition. Thus, sibutramine and its active metabolites do not evoke monoamine release (Table 1.5), do not inhibit monoamine oxidase, and have no relevant affinity (Ki > IpM) for a wide range of neurotransmitter receptors and related binding sites:

• 5-HT (5-HTi, 5-HTia, 5-HTib» 5-HT2a und 5-HT2c)»

• dopaminergic (Di, D2),

• muscarinic (M1/M2),

• Histaminic (Hi),

• Benzodiazepine and NMDA. (Heal and Cheetham, 1997).

Studies of the effects of selective noradrenaline or 5-HT reuptake inhibitors revealed that a synergistic action of sibutramine on both monoaminergic systems was essential for its anorectic properties. Thus, when either the selective noradrenaline reuptake inhibitor nisoxetine (3, 10 and 30 m g /k g ), or the selective 5-HT reuptake inhibitor, fluoxetine (3, 10 and 30 mg / kg), was given alone to rats, there was no reduction in food-intake over the 8 h dark period. However, when the two agents were

given in combination (30 mg / kg of each), food-intake decreased significantly (Jackson

et al. 1997). Similarly, given alone, nisoxetine and fluoxetine had no effect on energy expenditure but, in combination, they potently increased thermogenesis (Connoley et al.

1999).

Table 1.5 Effect o f sibutramine and its metabolites and various releasing agents on f^H]-NA, [^H]-5-HT, and [^H]-DA release from rat brain slices in vitro.

% Release at 100 nM 1000 nM 10 000 nM NA 5-HT DA NA 5-HT DA NA 5-HT DA Sibutramine and Metabolites 1 and 2 ^fenfluramine - - NO - 64 ND 82 282 ND d-amphetamine 57 - 56 135 - 122 162 136 138

- = non-significant effect on [ H] monoamine release. Data obtained from Heal and Cheetham 1997.

Jackson et al. (1997) reported that the hypophagic effect of sibutramine (10 m g /k g , p.o.) on male Sprague-Dawley rats, during the 8 h following drug

Chapter 1: General Introduction

partially antagonised by the (31-adrenoceptor antagonist, metoprolol, and the 5-HT

receptor antagonists, metergoline, ritanserin (selective 5-HT2a/2c) and SB200646

(selective 5-HT2b/2c)- However, it was not inhibited by the ^2-adrenoceptor antagonist

ICI 118,551 or by the a2-adrenoceptor antagonist RX 821002. Therefore, it was

concluded that Pi-adrenoceptors, 5-HT2A/2c-receptors and particularly ai-adrenoceptors

are involved in the appetite regulation exerted by sibutramine, which agrees with findings showing that activation of ai-adrenoceptors and 5-HT2A/2C-receptors by endogenous

noradrenaline and 5-HT, respectively, reduced food intake (area of study which is not within the scope o f this thesis).

1.4.3/ Am phetam ines versus sibutramine

Amphetamines and related anti-obesity agents have very high potential for abuse, which is partly attributed to the enhancement of dopaminergic transmission in the mesolimbic system. As a consequence, efforts were made to distinguish the pharmacological and physiological properties of sibutramine from those of drugs of abuse, and to confirm that sibutramine lacks the features which predict a liability to induce dependence.

• Abuse potential

The fact that sibutramine does not release dopamine (see Table 1.5) indicated that the drug should not present any of the addictive properties of amphetamines. Indeed, Cole

et al. (1998) showed that sibutramine does not have the potential of abuse characteristic of amphetamines. They tested the abuse potential of sibutramine on male recreational stimulant users using a series of validated subjective scales and questionnaires. Dextroamphetamine (20 and 30 mg) had greater stimulant and euphoric effects than placebo. In contrast, there was no difference between the effects of sibutramine ( 2 0 and

30 mg; 133 % and 200 % of the current maximum recommended daily dose) and placebo. The rank order of session enjoyment placed both doses of sibutramine last. In summary, this study indicated that sibutramine lacks the neurochemical features characteristic of a drug of abuse such as amphetamine. More recently, Schuh et al. (2000) provided data on

supratherapeutic doses (25 and 75 mg sibutramine). Again, sibutramine lacked amphetamine-type abuse liability. Moreover, acute administration of the highest dose produced unpleasant effects such as anxiety and confusion.

• Actions in the CNS

As shown in Table 1.5, in vitro data suggest that sibutramine and its metabolites do not release noradrenaline, 5-HT or dopamine, even at high concentrations. In contrast, amphetamines stimulate release of monoamines and, in the case of <i-amphetamine, there is no separation between the concentrations of d-amphetamine causing reuptake inhibition and release of [^H]-noradrenaline and [^H]-dopamine. Similarly, d-fenfluramine stimulates release of [^H]-5-HT from rat brain slices at 1000 nM (Table 1.5) and there is ony a three­ fold separation between the concentrations at which it acts as a releasing agent and a reuptake inhibitor.

Such differences have been investigated by in vivo microdialysis. Gundlah et al

(1997) suggested that it is possible to differentiate the effects of reuptake inhibitors such as sibutramine, with those of releasing agents, by analysing qualitatively the profile of neurotransmitter efflux after administration of test drugs. Sibutramine induces a dose dependent increase in efflux of noradrenaline (Wortley et al. 1999a, 1999b), 5-HT (Prow et al. 1997; Gundlah et al. 1997) and, at high doses, dopamine (Rowley et al. 2000). For all three monoamines, the effect of sibutramine is slow in onset, of prolonged duration and moderate magnitude. This is thought to be because monoamines accumulate extraneuronally and activate auto-receptors which blunt neuronal firing and neurotransmitter release. In contrast, the effects of releasing agents have a rapid onset independent of physiological control mechanisms. The maximum increase is reached generally within 20 to 40 minutes after injection and the effect is of relatively short duration (^/-amphetamine: Prow et al. 1997; Rowley et al. 2000; (/-fenfluramine, aminorex and phentermine: Tao et al. 2002).

Differences between releasing agents and reuptake inhibitors were also shown by modulating serotonergic neuronal function. Administration of the 5-HTia agonist,

Chapter 1: General Introduction

induced by the reuptake blockers fluoxetine and sibutramine (Gundlah et al. 1997; Tao et al. 2002). In contrast, administration of the 5-HTia agonist did not modulate the response to the releasing agents. The authors inferred that this indicated that the release of 5-HT induced by such agents is independent of neuronal firing rate. However, the possibility that the receptors were already saturated cannot be discarded. The use of the 5-HTia antagonist, WAY 1001635, could have been an interesting choice. Indeed, administration of this ligand should have increased the response to the reuptake blockers and would have been without effect on the response induced by the releasing agents.

Finally, another difference between the two classes of CNS agents was found by injecting the drugs during their local infusion into the hypothalamus (Gundlah et al.

1997; Tao et al. 2002). Systemic administration of high affinity reuptake inhibitors activated somatodendritic autoreceptors and attenuated the 5-HT response induced by their local infusion. In contrast, this did not happen with releasing agents, which supports the idea that the increase in 5-HT efflux after administration of releasing agents is independent from neuronal discharge. It is noteworthy that the authors observed that this experimental paradigm is only applicable to reuptake blockers with high affinity for the 5-HT transporter.

In conclusion, there are a number of differences between the actions of releasing agents and reuptake blockers on the monoamine systems. Most of these differences stem from the fact that the structure of reuptake inhibitors prevents them from being a substrate for the monoamine transporters. In contrast, releasing agents can be transported inside the neurones, where they mobilise monoamines from their storage vesicles, inducing an impulse-independent release of the neurotransmitters.