RO-3

Antagonism with dibenamine, D-600, and Ro 3-7894 to estimate dissociation constants and receptor reserves for cardiac adrenoceptors in isolated rabbit papillary muscles.[Pubmed:6290018]

Can J Physiol Pharmacol. 1982 Aug;60(8):1131-7.

In papillary muscles isolated from reserpinized rabbits, positive inotropic responses to the alpha (alpha)-adrenergic agonist, (-)-phenylephrine in the presence of 10(7) M timolol and the beta (beta)-adrenergic agonist. (-)-isoproterenol were antagonized with the irreversible alpha-adrenergic antagonist, dibenamine, the irreversible beta-adrenergic antagonist. Ro 3-7894, and the calcium blocker, D-600. D-600 was employed as a functional antagonist of both alpha- and beta-adrenoceptor responses. Dissociation constants (Ka values) for drug-receptor interactions were calculated by the method of Furchgott and used to estimate fractional receptor occupancy and agonist efficacies. Comparison of responses showed that the receptor reserve for cardiac beta-adrenoceptors was greater than for alpha-adrenoceptors. D-600 was an effective inhibitor of both cardiac alpha- and beta-adrenoceptor responses; however, estimates of KA and receptor reserves were similar to estimates using an irreversible antagonist for alpha-but not beta-adrenoceptors.

[Simultaneous improvement of mood and release of growth hormone by L-5-hydroxytryptophan (Ro 3-5940) in normal subjects (author's transl)].[Pubmed:313797]

Arzneimittelforschung. 1978;28(8):1291-2.

Infusion of a new soluble ester of L-5-hydroxytryptophan produced euphoria in 34/35 experiments in healthy subjects. Parallel measurements of growth hormone and mood changes showed a similar rise and fall of these two parameters in 8/11 subjects. These results indicate that central stimulatory serotoninergic mechanisms (in addition to the well-known dopaminergic and alpha-adrenergic stimulation) play a role in the control of growth hormone release.

Ro 3-4787, a new beta-adrenoceptor blocking agent: Studies in normal volunteers.[Pubmed:22454901]

Br J Clin Pharmacol. 1974 Apr;1(2):143-9.

1 A new beta-adrenoceptor blocking agent, Ro 3-4787, was administered orally to resting subjects. Peak levels of 106.2 +/- 15.5 ng/ml were reached after 20 mg given in the fasting state. After intravenous administration, an inverse rectilinear relationship was shown between the log dose (2 mg-20 mg) and the heart rate during vigorous exercise on a bicycle ergometer. 2 A double-blind study in five normal subjects using 0.03 mg/kg and 0.15 mg/kg showed that propranolol and Ro 3-4787 were equally effective in reducing the exercise heart rate. There was an inverse correlation between the log plasma level before exercise and the heart rate during exercise for both drugs over the range studied.

Painful purinergic receptors.[Pubmed:18042830]

J Pharmacol Exp Ther. 2008 Feb;324(2):409-15.

Multiple P2 receptor-mediated mechanisms exist by which ATP can alter nociceptive sensitivity following tissue injury. Evidence from a variety of experimental strategies, including genetic disruption studies and the development of selective antagonists, has indicated that the activation of P2X receptor subtypes, including P2X(3), P2X(2/3), P2X(4) and P2X(7), and P2Y (e.g., P2Y(2)) receptors, can modulate pain. For example, administration of a selective P2X(3) antagonist, A-317491, has been shown to effectively block both hyperalgesia and allodynia in different animal models of pathological pain. Intrathecally delivered antisense oligonucleotides targeting P2X(4) receptors decrease tactile allodynia following nerve injury. Selective antagonists for the P2X(7) receptor also reduce sensitization in animal models of inflammatory and neuropathic pain, providing evidence that purinergic glial-neural interactions are important modulators of noxious sensory neurotransmission. Furthermore, activation of P2Y(2) receptors leads to sensitization of polymodal transient receptor potential-1 receptors. Thus, ATP acting at multiple purinergic receptors, either directly on neurons (e.g., P2X(3), P2X(2/3), and P2Y receptors) or indirectly through neural-glial cell interactions (P2X(4) and P2X(7) receptors), alters nociceptive sensitivity. The development of selective antagonists for some of these P2 receptors has greatly aided investigations into the nociceptive role of ATP. This perspective highlights some of the recent advances to identify selective P2 receptor ligands, which has enhanced the investigation of ATP-related modulation of pain sensitivity.

Purinoceptors as therapeutic targets for lower urinary tract dysfunction.[Pubmed:16465177]

Br J Pharmacol. 2006 Feb;147 Suppl 2:S132-43.

Lower urinary tract symptoms (LUTS) are present in many common urological syndromes. However, their current suboptimal management by muscarinic and alpha(1)-adrenoceptor antagonists leaves a significant opportunity for the discovery and development of superior medicines. As potential targets for such therapeutics, purinoceptors have emerged over the last two decades from investigations that have established a prominent role for ATP in the regulation of urinary bladder function under normal and pathophysiological conditions. In particular, evidence suggests that ATP signaling via P2X(1) receptors participates in the efferent control of detrusor smooth muscle excitability, and that this function may be heightened in disease and aging. ATP also appears to be involved in bladder sensation, via activation of P2X(3) and P2X(2/3) receptors on sensory afferent neurons, both within the bladder itself and possibly at central synapses. Such findings are based on results from classical pharmacological and localization studies in non-human and human tissues, knockout mice, and studies using recently identified pharmacological antagonists--some of which possess attributes that offer the potential for optimization into candidate drug molecules. Based on recent advances in this field, it is clearly possible that the development of selective antagonists for these receptors will occur that could lead to therapies offering better relief of sensory and motor symptoms for patients, while minimizing the systemic side effects that limit current medicines.