The relative potencies of methotrimeprazine, (+)‐methotrimeprazine, (±)‐10‐(3‐dimethylamino‐2‐methylpropyl)‐2‐valeroyl phenothiazine hydrochloride (M & B 18,706) and (+)‐M & B 18,706 in reducing the pressor action of noradrenaline in the spinal cat, reducing intercollicular decerebrate rigidity, and muscle spindle afferent activity have been studied. Methotrimeprazine was eight times as potent as (+)‐methotrimeprazine in reducing the pressor action of noradrenaline and six times as potent in reducing decerebrate rigidity. M & B 18,706 was also eight times as potent as (+)‐M & B 18,706 in reducing the pressor action of noradrenaline and six times as potent in reducing decerebrate rigidity. For the above compounds and chlorpromazine there was a significant correlation between the effective doses for the inhibition of the pressor action of noradrenaline and for the reduction of decerebrate rigidity. The doses which reduced decerebrate rigidity were similar to those that reduced muscle spindle afferent discharge. It is likely that these drugs reduce decerebrate rigidity by inhibiting fusimotor activity. Desipramine increased decerebrate rigidity and increased spindle afferent discharge. It is thought that the phenothiazine derivatives studied reduce decerebrate rigidity and spindle afferent discharge by inhibiting receptors for noradrenaline in the central nervous system.

(±)‐10‐(3‐Dimethylamino‐2‐methylpropyl)‐2‐valeroylphenothiazine hydrochloride (M & B 18,706) has been compared with dimethothiazine, chlorpromazine, diazepam and baclofen for potency in reducing decerebrate rigidity in the cat and rat and for activity in causing ataxia or sedation. When given intravenously M & B 18,706 had seven times the potency of dimethothiazine and one‐half the potency of chlorpromazine in reducing the rigidity of the intercollicular decerebrate cat. When administered orally M & B 18,706 and chlorpromazine were equi‐potent in reducing rigidity but M & B 18,706 was less effective than chlorpromazine in producing ataxia in this species. In the rat, M & B 18,706 had one‐quarter the potency of chlorpromazine for reducing decerebrate rigidity but had from 1/20th to 1/200th its potency in tests for sedative or tranquillizing activity. M & B 18,706, like dimethothiazine and chlorpromazine, had little effect on the rigidity of ischaemic decerebrate cats and failed to inhibit polysynaptic spinal reflexes. M & B 18,706 had intravenous potency comparable to chlorpromazine in reducing the pressor action of noradrenaline in the spinal cat.