Table 1.
A summary of the biological activities reported for intermediaries isolated from the indole-diterpene biosynthetic pathway and some synthetic derivatives.
| Compound Name | Toxicity as Per Biological Activity on Mice (mg of Compound/kg of Body Weight) | Observation on Mice | Biological Activity on BK/Maxi or hSlo Channel | Biological Activity on Animal Model (EMG Activity/Observation in Sheep) | Reference |
|---|---|---|---|---|---|
| Lolitrem A | 2 mg/kg | Severe and prolonged tremor | ¯ | ¯ | [44] |
| Lolitrem B | 0.5 to 8.0 mg/kg | Severe and prolonged tremor | IC50 = 4 nM (No recovery after wash out) | At 70 µg/kg dose, tremors were observed after 15 min and slowly increased in severity lasting for duration of 12 h. The reticulum and rumen showed inhibition after 20–30 min, coinciding with tremors. | [16,35,41] |
| 31-epi-lolitrem B | 4 mg/kg | Nontremorgenic | IC50 = 50 nM (>50% recovery after 10 min) | The lolitrem B isomer was administered at a dose of 70 µg/kg and there was no effect either on the skeletal muscle EMG activity or EMG activity of the reticulum and rumen. | [33,41,45] |
| Lolitrem E | 2 mg/kg | Nontremorgenic | IC50 = 6 nM (No recovery after wash out) | ¯ | [20,41] |
| Lolitrem E acetate | 16 mg/kg | Weakly tremorgenic | IC50 = 2 nM (No recovery after wash out) | ¯ | [28,41] |
| 31-epi-lolitrem Fa | 4 mg/kg | Slightly less tremorgenic than lolitrem B | ¯ | ¯ | [46] |
| Lolitrem Fa | 4 mg/kg | Slightly less tremorgenic than lolitrem B | IC50 = 8 nM (No recovery after wash out) | ¯ | [41,46] |
| Lolitrem M | Nontremorgenic | IC50 = 78 nM (>50% recovery after 10 min) | ¯ | [41] | |
| Paxilline | 4 to 8 mg/kg and an 80 mg/kg dose | Severe but short term tremorgenicity compared to lolitrem B | Complete inhibition = 1 µM (recovery after wash out) Fraction current blocked by 10 nM = 70% (recovery after wash out) |
At 1.0 mg/kg dose, moderate to strong tremors; the onset was immediate after 2 min administration; tremors gradually disappeared over the next hour. EMG activity showed both excitatory and inhibitory on the reticulum and rumen. Also, within a minute of infusion, elevations of the EMG activity coincided with induction of marked tremoring. | [33,36,38,47] |
| 13-Desoxypaxilline | 8 mg/kg | Nontremorgenic | < 50% inhibition = 30 µM | ¯ | [38] |
| α-Paxitriol | 100 mg/kg | Lethargy and rough coats, also normal activities such as walking, rearing and preening were greatly reduced for several hours. Animals recovered to normal by 24 h post-injection. | ¯ | ¯ | [47] |
| β-Paxitriol | 100 mg/kg | Lethargy and rough coats, also normal activities such as walking, rearing and preening were greatly reduced for several hours. Animals recovered to normal by 24 h post-injection. | ¯ | ¯ | [47] |
| Lolitriol | 20 mg/kg | Nontremorgenic | IC50 = 196 nM (>50% recovery after 10 min) | ¯ | [47] |
| Lolitriol acetate | - | Nontremorgenic | IC50 = 43 nM (>50% recovery after 10 min) | ¯ | [41] |
| Lolitriol and β-Paxitrol | As a mixture: 16 mg/kg and 100 mg/kg respectively (200 µL dosage) | The single administration of both β-paxitriol and the nontremorgenic lolitriol proved lethal after an initial period of lethargy | - | - | [47] |
| Lolilline | 8 mg/kg | Nontremorgenic | - | - | [43] |
| 6,7-dehydroterpendole A | 8 mg/kg | Produced more intense tremors than terpendole C and K at the same dose level | - | - | [48,49] |
| Terpendole C | 4 mg/kg and 8 mg/kg | A fast-acting tremorgen that produced more intense tremors than paxilline, 11-hydroxy12,13-epoxyterpendole K and 6,7-dehydro-11-hydroxy-12, 13 epoxyterpendole A at the same dose level, but the activity ceased after 2 h, as compared to paxilline which ceased after 6 h. | ¯ | ¯ | [43,48] |
| Terpendole D, E, F, G, H and I | 8 mg/kg | Nontremorgenic | ¯ | ¯ | [28] |
| Terpendole K | 8 mg/kg | Produced more intense tremors than paxilline, 11-hydroxy12,13-epoxyterpendole K and 6,7-dehydro-11-hydroxy-12,13 epoxyterpendole A at the same dose level | ¯ | ¯ | [48] |
| Terpendole M | 8 mg/kg | Weakly tremorgenic | ¯ | ¯ | [50] |
| 6,7-dehydro-11-hydroxy-12,13 epoxyterpendole A and 11-hydroxy12,13-epoxyterpendole K | 8 mg/kg | Mild tremors | ¯ | ¯ | [48,49] |
| Mixture of 88.3% Penitrem A, 6.4% Penitrem B, 5.3% Penitrem E | ¯ | ¯ | A dose of 5.5 mg/kg showed no significant skeletal EMG activity, although exhibited strong inhibition on the reticulum and rumen. This was apparent at 15 to 30 min and lasted 2 h. The maximum period of inhibition coincided with the period of greatest tremoring. | [33,51] | |
| Penitrem A | 0.75 mg/kg (dose range 0.5 mg/kg to 1.5 mg/kg) | Elicited moderate tremors. Tremor duration reported as several hours. | Fraction current blocked by 10 nM = 100% (no recovery after wash out) | Tremorgenic observation in sheep when given at a dose of 20 µg/kg intravenously. | [36,52,53,54] |
| Penitrem E | 2.25 mg/kg (dose range 1.0 mg/kg to 3.6 mg/kg) | Elicited moderate tremors. Tremor duration reported as several hours. No difference to penitrem A in the rates of onset of tremors observed, and the symptomatology were like-wise similar. | - | - | [54] |
| Paspaline | ¯ | ¯ | Slight inhibition at concentrations up to 1 µM | ¯ | [38] |
| Paspalinine | 8 mg/kg | Short duration tremors | Fraction current blocked by 10 nM = 100% (no recovery after wash out) | ¯ | [28,36,55,56] |
| Paspalicine | 250 mg/kg | Nontremorgenic | Fraction current blocked by 10 nM = 83% (recovery after wash out) | ¯ | [36,55,57] |
| Paspalitrems | 14 mg/kg | Short duration tremors | Fraction current blocked by 10 nM of paspalitrem A and paspalitrem C = 98% and 100% respectively (no recovery after wash out) | ¯ | [36,55] |
| Aflatrem | 1 mg/kg (dose range 0.5 mg/kg to 4.0 mg/kg) |
Short duration tremors | Fraction current blocked by 10 nM = 100% (no recovery after wash out) | ¯ | [16,36] |
| Janthitrem A | 4 mg/kg | Tremor duration was reported as 8 h and peaked at 15 min. Tremors produced were more intense than janthitrem B, from 2 h post exposure. | ¯ | ¯ | [58] |
| Janthitrem B | 6 mg/kg | Tremor duration reported as 6 h and peaked at 30 min. Un-coordination and hypersensitivity to sound and touch is also reported. | ¯ | ¯ | [58,59,60] |
a) Lolitrem F and 31-epi-lolitrem F have been reported to have a similar but slightly reduced tremorgenic activity compared to that reported for lolitrem B; however, Munday-Finch et al. assume that impurities present in lolitrem F and 31-epi-lolitrem F could have caused the slightly reduced activity [46].