An Assessment of the Partial Agonist Activity Ofro 31
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Br. J. clin. Pharmac. (1987), 24, 571-580 An assessment of the partial agonist activity of Ro 31-1118, flusoxolol and pindolol in man P. M. McCAFFREY, J. G. RIDDELL & R. G. SHANKS Department of Therapeutics and Pharmacology, The Queen's University of Belfast, Belfast 1 The effects of single oral doses of three ,-adrenoceptor partial agonists (Ro 31-1118, flusoxolol and pindolol), two P-adrenoceptor antagonists (propranolol and atenolol), two 3-adrenoceptor agonists (salbutamol and prenalterol) and placebo on sleeping heart rate, quality of sleep, supine heart rate, exercise heart rate, blood pressure, forearm blood flow and finger tremor were studied in eight healthy male volunteers. 2 Sleeping heart rate was increased by Ro 31-1118, flusoxolol, pindolol, salbutamol and prenalterol and decreased by propranolol and atenolol. 3 None of the drugs studied affected quality of sleep. 4 Supine heart rate was increased by flusoxolol, prenalterol and salbutamol, unaffected by Ro 31-1118 and pindolol and reduced by propranolol and atenolol. 5 Exercise heart rate was reduced by both 3-adrenoceptor antagonists and the three partial agonists and unaffected by salbutamol and prenalterol. 6 Systolic blood pressure was increased by Ro 31-1118, flusoxolol, salbutamol and prenalterol, unaffected by pindolol and reduced by propranolol and atenolol. Diastolic blood pressure was reduced by salbutamol and prenalterol. 7 Forearm blood flow was increased by Ro 31-1118, salbutamol and prenalterol, unchanged by pindolol and flusoxolol and decreased by atenolol and propranolol. 8 Finger tremor was increased by Ro 31-1118, flusoxolol, pindolol, salbutamol and prenalterol. 9 ,3-adrenoceptor partial agonists have different effects on the cardiovascular system and finger tremor to ,-adrenoceptor antagonists. 10 While Ro 31-1118 and flusoxolol are antagonists mainly at the P,-adrenoceptor they have agonist activity at both 13l- and 132 adrenoceptors. 11 While pindolol is a non-selective antagonist its agonist activity is mainly at the 132- adrenoceptor. Keywords partial agonist activity pindolol flusoxolol Ro 31-1118 13-adrenoceptor antagonist Introduction 13-adrenoceptor antagonists have a number of and partial agonist activity (Fitzgerald, 1984). additional properties including cardioselectivity, To demonstrate partial agonist activity ,B-adreno- lipid solubility, membrane stabilising activity ceptor antagonists must be shown to cause both Correspondence to: Dr J. G. Riddell, Department of Therapeutics and Pharmacology, The Queen's University of Belfast, The Whitla Medical Building, 97 Lisburn Road, Belfast BT9 7BL 571 572 P. M. McCaffrey, J. G. Riddell & R. G. Shanks measurable agonist and antagonist responses. Methods By definition the agonist activity should never cause as great a biological effect as that pro- Observations were made in 16 healthy male duced by a full agonist, such as isoprenaline, no subjects who gave informed consent after the matter how high the dose given. The observed procedures involved had been fully explained to effects of 1-adrenoceptor agonist and antago- them. The studies were approved by the Research nist activity depend on the degree ofsympathetic Ethical Committee of the Queen's University of drive. Agonist effects are most easily seen when Belfast. the level of sympathetic tone is low such as during sleep and antagonist activity predomi- Study 1 nates when the level of sympathetic tone is high Eight healthy male volunteers (mean age 23 ± 4 such as during exercise. years, mean weight 77 ± 7 kg) took part in the The classical studies of partial agonist activity study. At weekly intervals, double-blind and have been performed in experimental animals in following a randomised Latin Square design each which the effects of reflex sympathetic stimu- received on separate occasions, single oral doses lation and endogenous catecholamines have of Ro 31-1118 160 mg, flusoxolol 80 mg, pindolol been removed (Barrett & Carter, 1970; Bilski et 10 mg, atenolol 50 mg, propranolol 80mg, salbu- al., 1979). Demonstration of partial agonist tamol 8 mg, prenalterol 50 mg and placebo. activity in man has been more difficult because In the late afternoon on each study day elec- reflexes are intact and it is not possible to trodes were attached to the anterior chest wall of remove endogenous catecholamines. However a the volunteer in a modified lead II position and number of studies in man have shown that ,B- to an Oxford Medilog 4-24 miniature tape adrenoceptor partial agonists differ from 1- recorder worn in a leather case at the waist. The adrenoceptor antagonists by causing less reduc- drugs were administered orally between 23.00 h tion in supine heart rate and cardiac output and 24.00 h. Volunteers retired to bed within 30 (Svendsen et al., 1979; 1981; Taylor et al., 1982) min of drug administration. They were asked to and having flatter dose-response curves for press the event button when they went to bed, reduction of exercise tachycardia (McDevitt et when they awoke in the morning and if they al., 1977). awoke during the night. The tape recorder was Ro 31-1118 (1 - (4 - [2 - (4 - fluorophenethy- removed the following morning. The volunteer loxy) - ethoxy] phenoxy) - 3 - isopropylamino completed a St Mary's Hospital sleep question- - 2 - propanol hydrochloride is a long acting naire (Ellis et al., 1981) and a visual analogue cardioselective 3-adrenoceptor partial agonist scale for assessing the quality ofsleep. The visual (Blaber et al., 1983; O'Connor et al., 1985) and analogue scale was 10 cm long, with 'the best flusoxolol is its S-enantiomer. Pindolol is a non night's sleep ever' written at one and 'the worst cardioselective partial agonist though it has been night's sleep ever' written at the other end. The suggested that its agonist activity is mainly at the same verbal instructions were given each day: 132-adrenoceptor (Clark, 1984). Atenolol and 'Regarding how you slept last night please mark propranolol are 3-adrenoceptor antagonists, the line between the best night's sleep and the with and without cardioselectivity respectively. worst night's sleep ever. Your normal night's Salbutamol is a 132-adrenoceptor agonist sleep would be in the middle'. The tape was (Hartley et al., 1968) and prenalterol is a pre- analysed using the Oxford Instruments ECG dominately 131-adrenoceptor agonist but has Analysis system. Side effects were elicited by the been shown to have some activity at the 12- written question 'Did you notice anything adrenoceptor (Mattsson et al., 1982a,b). unusual?' The present studies were undertaken to Hourly mean heart rates for the 8 h after demonstrate the partial agonist activity of Ro treatment were compared using the SPSS para- 31-1118, flusoxolol and pindolol in man and to metric analysis of variance and Duncan's mul- compare their effects on the cardiovascular test. The results of the system and finger tremor to those of proprano- tiple range sleep question- lol, atenolol, salbutamol, prenalterol and naire and visual analogue scale were analysed placebo. Fixed oral doses were used and no using Friedman's two way analysis of variance. formal dose-response observations were made Statistically significant differences were con- because of the number of drugs studied. The sidered to exist when P was < 0.05. Results are doses of those drugs with 13-adrenoceptor expressed as the mean ± the s.d.. antagonist activity were those which have been shown to have approximately equal 13-adreno- Study 2 ceptor blocking activity. Eight healthy male volunteers (mean age 22 + Partial agonist activity ofRo 31-1118, flusoxolol and pindolol 573 0.5 years, mean weight 74 ± 11 kg) took part in the study. At weekly intervals, double-blind and following a randomised Latin Square design each received on separate occasions, single oral doses 160 mg, flusoxolol 80 mg, pindolol * of Ro 31-1118 * * FF-* * *4F* * 10 mg, propranolol 80 mg, atenolol 50 mg, salbu- +4+4+4+04+ en 00 00 00 00 00 _, tamol 8 mg, prenalterol 50 mg and placebo. All +1 +1 +1 +1 +1 +1 +1 +1 studies were carried out in the morning in a mmtn££0 £F a1~ll~ m0 \0 \0 temperature controlled room (24-25' C). On the morning of the study the volunteer had a light * * * 4+ breakfast without caffeine. After 30 min of supine 41+4+i4+ 4+4+i 4+0-C 0N 00 O ON C., N- rest, heart rate, blood pressure, finger tremor +l +1 +1 +1 +1 +1 +1 +1 00 t ce and forearm blood flow were measured. Heart n v) tn r011 - rate was measured from a direct writing electro- cardiogram and blood pressure using a Hawksley * * random zero sphygmomanometer. The Korot- CO koff fourth sound was used for the diastolic +1 +1 +1+1+1+1+1+1 ** blood pressure. Finger tremor was measured tn t n 10 to using a piezo electric accelerometer attached to the dorsum of the middle finger of the left hand a) CO 4+* (Arnold & McDevitt, 1983; Riddell et al., 1986). 44+ot- c- Forearm blood flow was measured using venous +l +1 +1 +1 +1 +1 +1 +1 .0CO occlusion plethysmography (Riddell et al., 1986). CZ was .0 oo oo oo N Forearm vascular resistance calculated by 00 .0 dividing mean arterial blood pressure by fore- CO U4 o C.0 twn tw)£ tb arm blood flow. 0 4+0C>4+ (N 41+4+* '-400 O ON ON 00 The measurements were repeated after a +l +1 +1 +1 +1 +1 +1 +1 4- further 15 min. The drugs were then administered c) a..C; orally with 30 ml of water. The above measure- v) ments were repeated at 30 min intervals for 3 h. ra .0 tDn tn 11 'I to An exercise step test was then performed which 4+ 0'e cm involves stepping on and off a box 46 high, 32 +1 +1** +1 +1 +1 +1+l +1 times min- for 3 min.